Prevalence of iron deficiency and anemia in pediatric heart transplant recipients.

INTRODUCTION: The prevalence of iron deficiency and anemia in the setting of modern-day maintenance immunosuppression in pediatric heart transplant (HTx) recipients is unclear. The primary aim was to determine the prevalence of iron deficiency (serum ferritin < 30 ng/mL ± transferrin saturation < 20%) and anemia per World Health Organization diagnostic criteria and associated risk factors. METHODS: Single-center, cross-sectional analysis of 200 consecutive pediatric HTx recipients (<21 years old) from 2005 to 2021. Data were collected at 1-year post-HTx at the time of annual protocol biopsy. RESULTS: Median age at transplant was 3 years (IQR .5-12.2). The median ferritin level was 32 ng/mL with 46% having ferritin < 30 ng/mL. Median transferrin saturation (TSAT) was 22% with 47% having TSAT < 20%. Median hemoglobin was 11 g/dL with 54% having anemia. Multivariable analysis revealed lower absolute lymphocyte count, TSAT < 20%, and estimated glomerular filtration rate <75 mL/min/1.73 m2 were independently associated with anemia. Ferritin < 30 ng/mL in isolation was not associated with anemia. Ferritin < 30 ng/mL may aid in detecting absolute iron deficiency while TSAT < 20% may be useful in identifying patients with functional iron deficiency ± anemia in pediatric HTx recipients. CONCLUSION: Iron deficiency and anemia are highly prevalent in pediatric HTx recipients. Future studies are needed to assess the impact of iron deficiency, whether with or without anemia, on clinical outcomes in pediatric HTx recipients.

A quantitative assessment of renal function utilizing albuminuria in pediatric heart transplant recipients.

INTRODUCTION: Kidney disease is common after pediatric heart transplantation. Serum creatinine-based glomerular filtration rate is the most frequently reported measure of kidney function. Albuminuria is an additional marker of kidney dysfunction and is not well described in this population. In this study, we evaluate the prevalence and degree of albuminuria and describe clinical factors associated with albuminuria in a cohort of pediatric heart transplant recipients. METHODS: This was a cross-sectional study of pediatric heart transplant recipients. Albuminuria was assessed using spot urine albumin-to-creatinine ratio collected at the most recent annual screening cardiac catheterization through August 2019. RESULTS: In 115 patients at a median duration of 10.2 years post-transplant, 39% had albuminuria. Stage 3 or greater chronic kidney disease was present in 6%. The immunosuppressive regimen at the time of measurement contained a calcineurin inhibitor (CNI) in 88% and a proliferation signal inhibitor (PSI) in 62%. In multivariable modeling, lower eGFR, PSI use, and younger age at transplant were associated with higher levels of albuminuria, whereas CNI use was associated with lower levels of albuminuria. CONCLUSION: Albuminuria is a prevalent finding in medium-term follow up of pediatric heart transplant recipients, reflecting kidney injury, and is associated with other markers of kidney dysfunction, such as low eGFR. Younger age at transplant, lower eGFR, and PSI use were among the associations with albuminuria.

Successful implementation of telehealth visits in the paediatric heart failure and heart transplant population.

The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) and Pediatric Heart Transplant Society (PHTS) convened a working group at the beginning of 2020 during the COVID-19 pandemic, with the aim of using telehealth as an alternative medium to provide quality care to a high-acuity paediatric population receiving advanced cardiac therapies. An algorithm was developed to determine appropriateness, educational handouts were developed for both patients and providers, and post-visit surveys were collected. Telehealth was found to be a viable modality for health care delivery in the paediatric heart failure and transplant population and has promising application in the continuity of follow-up, medication titration, and patient education/counselling domains.

Analysis of Platelet Function Testing in Children Receiving Aspirin for Antiplatelet Effects.

Aspirin (ASA) remains the most common antiplatelet agent used in children. VerifyNow Aspirin Test® (VN) assesses platelet response to ASA, with therapeutic effect defined by the manufacturer as ≤ 549 aspirin reaction units (ARU). Single-center, observational, analysis of 195 children (< 18 years-old) who underwent first VN between 2015 and 2020. Primary outcome was proportion of patients with ASA biochemical resistance (> 549 ARU). Secondary outcomes included incidence of new clinical thrombotic and bleeding events during ≤ 6 months from VN in those who received ASA monotherapy (n = 113). Median age was 1.8 years. Common indications for ASA included cardiac anomalies or dysfunction (74.8%) and ischemic stroke (22.6%). Median ASA dose before VN was 4.6 mg/kg/day. Mean VN was 471 ARU. ASA biochemical resistance was detected in 14.4% (n = 28). Of 113 patients receiving ASA monotherapy, 14 (12.4%) had a thrombotic event and 2 (1.8%) had a bleeding event. Mean VN was significantly higher at initial testing in patients experiencing thrombotic event compared to those without thrombosis (516 vs 465 ARU, [95% CI: 9.8, 92.2], p = 0.02). Multivariable analysis identified initial VN ASA result ≥ 500 ARU at initial testing as the only significant independent risk factor for thrombosis (p < 0.01). VN testing identifies ASA biochemical resistance in 14.4% of children. VN ASA ≥ 500 ARU rather than ≥ 550 ARU at initial testing was independently associated with increased odds of thrombosis. Designated cut-off of 550 ARU for detecting platelet dysfunction by ASA may need reconsideration in children.

Mycophenolic acid therapeutic drug monitoring using area under the curve in pediatric heart transplant recipients.

INTRODUCTION: Pharmacokinetics of mycophenolic acid (MPA) display substantial interpatient variability, with up to 10-fold difference of exposure in individual patients under a fixed-dose regimen. MPA trough level (C0) monitoring is common in clinical practice but has not proven sufficiently informative in predicting MPA exposure or patient outcomes, especially in children. No limited sampling strategies (LSSs) have been generated from pediatric heart transplant (HTx) recipients to estimate MPA AUC. METHODS: Single-center, observational analysis of 135 de novo pediatric HTx recipients ≤21 years old who underwent MPA AUC between 2011 and 2021. RESULTS: Median age was 4 years (IQR .6-12.1). Median time from transplant to MPA AUC sampling was 15 days (IQR 11-19). MMF doses (mg or mg/day) had low, negative Pearson correlation coefficients (r) while doses adjusted for weight or body surface area had low correlation with Trapezoidal MPA AUC0-24 h (r = .3 and .383, respectively). MPA C0 had weak association (r = .451) with Trapezoidal MPA AUC0-24 h . LSS with two pharmacokinetic sampling time points at 90 (C3 ) and 360 (C5 ) min after MMF administration (estimated AUC0-24 h  = 32.82 + 4.12 × C3  + 11.53 × C5 ) showed strong correlation with Trapezoidal MPA AUC0-24 h (r = .87). CONCLUSION: MMF at fixed or weight-adjusted doses, as well as MPA trough levels, correlate poorly with MPA AUC0-24 h . We developed novel LSSs to estimate Trapezoidal MPA AUC from a large cohort of pediatric HTx recipients. Validation of our LSSs should be completed in a separate cohort of pediatric HTx recipients.

Assessment of the adverse effects of sirolimus versus everolimus in pediatric heart transplant recipients.

BACKGROUND: Literature is limited comparing adverse effects (AEs) of the proliferation signal inhibitors (PSIs) sirolimus (SRL) and everolimus (EVL) in pediatric heart transplant (HTx) recipients. METHODS: Single-center, observational cohort analysis assessing first use of SRL or EVL in pediatric HTx recipients <21 years of age with up to 2 years follow-up between 2009 and 2020. RESULTS: Eighty-seven patients were included, with 52 (59.8%) receiving EVL and 35 (40.2%) receiving SRL. Tacrolimus with PSI was the most common regimen. Intergroup comparison revealed lower baseline estimated glomerular filtration rate (eGFR) and greater increase in eGFR from baseline to 6 months and latest follow-up in SRL cohort compared to EVL cohort. There was greater increase in HDL cholesterol in SRL cohort compared to EVL cohort. Intragroup analysis revealed eGFR and HDL cholesterol increased significantly within SRL cohort, triglycerides and glycosylated hemoglobin increased in EVL cohort, and LDL cholesterol and total cholesterol increased in both cohorts (all p < .05). There were no differences in hematological indices or rates of aphthous ulcers, effusions, or infections between cohorts. Incidence of proteinuria was not significantly different among those screened within cohorts. Of those included in our analysis, one patient in SRL cohort (2.9%) and two in EVL cohort (3.8%) had PSI withdrawn due to AE. CONCLUSION: Low-dose PSIs in calcineurin inhibitor minimization regimens appear well-tolerated with low withdrawal rate secondary to AE in pediatric HTx recipients. While incidence of most AE was similar between PSI, our results suggest EVL may be associated with less favorable metabolic impact than SRL in this population.

Early Clinical Experience with Dapagliflozin in Children with Heart Failure.

Pediatric heart failure (HF) is associated with significant morbidity and mortality. Medical treatment for pediatric HF is largely derived from adult studies. Previously, there has been no described use of dapagliflozin in pediatric HF patients. We describe our single-center experience using dapagliflozin in addition to standard HF medical therapy in 38 pediatric HF patients since January 2020. Median age was 12.2 years (interquartile range 6.2-17.5). Majority of patients had dilated cardiomyopathy (68.4%) and reduced left ventricular ejection fraction (LVEF) of 40% or less (65.8%). HF regimens commonly included sacubitril/valsartan, beta-blocker, mineralocorticoid receptor antagonist, and loop diuretic. Median follow-up from dapagliflozin initiation for the whole cohort was 130 days (IQR 76-332). Median B-type natriuretic peptide decreased significantly from 222 to 166 pg/mL at latest clinical follow-up (P = .04). Estimated glomerular filtration rate trended lower at latest follow-up but was not significant from baseline. There were no clinically significant changes in blood chemistries or vital signs after initiation of dapagliflozin. No patients experienced symptomatic hypoglycemia or hypovolemia. Six patients (15.8%) experienced a symptomatic urinary tract infection necessitating antibiotic treatment. In a separate analysis of 16 patients with dilated cardiomyopathy who received dapagliflozin for a median of 313 days (IQR 191-414), median LVEF increased significantly from 32 to 37.2% (P = .006). Dapagliflozin, when added to a background of guideline-directed medical therapy, appears well tolerated in children with HF. Larger studies are needed to evaluate safety and efficacy of dapagliflozin in this population.

SARS-CoV-2 RNA positive pediatric organ donors: A case report.

BACKGROUND: Preliminary evidence suggests that non-lung organ donation from resolved, asymptomatic or mildly symptomatic SARS-CoV-2 infected adults may be safe. However, several biological aspects of SARS-CoV-2 infection differ in children and the risk for transmission and outcomes of recipients from pediatric donors with SARS-CoV-2 infection are not well described. METHODS: We report two unvaccinated asymptomatic pediatric non-lung organ deceased donors who tested positive for SARS-CoV-2 RNA by RT-PCR. Donor One unexpectedly had SARS-CoV-2 RNA detected in nasopharyngeal swab and plasma specimens at autopsy despite several negative tests (upper and lower respiratory tract) in the days prior to organ recovery. Donor Two had SARS-CoV- 2 RNA detected in multiple nasopharyngeal swabs but not lower respiratory tract specimens (endotracheal aspirate and bronchoalveolar lavage) during routine surveillance prior to organ recovery and was managed with remdesivir and monoclonal antibodies prior to organ recovery. RESULTS: Two hearts, two livers and four kidneys were successfully transplanted into seven recipients. No donor to recipient transmission of SARS-CoV-2 was observed and graft function of all organs has remained excellent for up to 7 months of followup. CONCLUSIONS: Due to the persistent gap between organ availability and the number of children waiting for transplants, deceased pediatric patients with non-disseminated SARS-CoV-2 infection, isolated to upper and/or lower respiratory tract, should be considered as potential non-lung organ donors.

Treating Pediatric Myocarditis with High Dose Steroids and Immunoglobulin.

There is considerable variability in practice among pediatric centers for treatment of myocarditis. We report outcomes using high dose steroids in conjunction with IVIG. This is a single center retrospective study of children < 21 years of age diagnosed with myocarditis and treated with high dose steroids and IVIG from January 2004-April 2021. Diagnostic criteria for myocarditis included positive endomyocardial biopsy, cardiac magnetic resonance (CMR) imaging meeting Lake Louise criteria, or strictly defined clinical diagnosis. Forty patients met inclusion criteria. Median age at diagnosis was 11.6 years (0.7-14.6). Diagnosis was made clinically in 70% of cases (N = 28), by CMR in 12.5% (N = 5) and by biopsy in 17.5% (N = 7). Median ejection fraction (EF) at diagnosis was 35% (IQR 24-48). Median duration of IV steroids was 7 days (IQR 4-12) followed by an oral taper. Median cumulative dose of IV immunoglobulin (IVIG) was 2 g/kg. There were no serious secondary bacterial infections after steroid initiation. Ten patients (25%) required mechanical circulatory support. Overall transplant free survival was 92.5% with median follow-up of 1 year (IQR 0-6 years). Six patients required re-admission for cardiovascular reasons. By 3 months from diagnosis, 70% of patients regained normal left ventricular function. High dose steroids in conjunction with IVIG to treat acute myocarditis can be safe without significant infections or long-term side effects. Our cohort had excellent recovery of ventricular function and survival without transplant. Prospective comparison of a combination of high dose steroids with IVIG versus other therapies is needed.

Waitlist and posttransplant outcomes of critically ill infants awaiting heart transplantation managed without ventricular assist device support.

BACKGROUND: Infants listed for heart transplant are at high risk for waitlist mortality. While waitlist mortality for children has decreased in the current era of increased ventricular assist device use, outcomes for small infants supported by ventricular assist device remain suboptimal. We evaluated morbidity and survival in critically ill infants listed for heart transplant and managed without ventricular assist device support. METHODS: Critically ill infants (requiring ≥1 inotrope and mechanical ventilation or ≥2 inotropes without mechanical ventilation) listed between 2008 and 2019 were included. During the study period, infants were managed primarily medically. Mechanical circulatory support, specifically extracorporeal membrane oxygenation, was utilized as "rescue therapy" for decompensating patients. RESULTS: Thirty-two infants were listed 1A, 66% with congenital heart disease. Median age and weight at listing were 2.2 months and 4.4 kg, with 69% weighing <5 kg. At listing, 97% were mechanically ventilated, 41% on ≥2 inotropes, and 25% under neuromuscular blockade. Five patients were supported by ECMO after listing. A favorable outcome (transplant or recovery) was observed in 84%. One-year posttransplant survival was 92%. Infection was the most common waitlist complication occurring in 75%. Stroke was rare, occurring in one patient who was supported on ECMO. Renal function improved from listing to transplant, death, or recovery (eGFR 70 vs 87 ml/min/1.73m2 , p = .001). CONCLUSION: A strategy incorporating a high threshold for mechanical circulatory support and acceptance of prolonged mechanical ventilation and neuromuscular blockade can achieve good survival and morbidity outcomes for critically ill infants listed for heart transplant.

Association Between Cytomegalovirus Serostatus, Antiviral Therapy, and Allograft Survival in Pediatric Heart Transplantation.

Background: Cytomegalovirus (CMV) is an important complication of heart transplantation and has been associated with graft loss in adults. The data in pediatric transplantation, however, is limited and conflicting. We conducted a large-scale cohort study to better characterize the relationship between CMV serostatus, CMV antiviral use, and graft survival in pediatric heart transplantation. Methods: 4,968 pediatric recipients of solitary heart transplants from the Scientific Registry of Transplant Recipients were stratified into three groups based on donor or recipient seropositivity and antiviral use: CMV seronegative (CMV-) transplants, CMV seropositive (CMV+) transplants without antiviral therapy, and CMV+ transplants with antiviral therapy. The primary endpoint was retransplantation or death. Results: CMV+ transplants without antiviral therapy experienced worse graft survival than CMV+ transplants with antiviral therapy (10-year: 57 vs 65%). CMV+ transplants with antiviral therapy experienced similar survival as CMV- transplants. Compared to CMV seronegativity, CMV seropositivity without antiviral therapy had a hazard ratio of 1.21 (1.07-1.37 95% CI, p-value = .003). Amongst CMV+ transplants, antiviral therapy had a hazard ratio of .82 (0.74-.92 95% CI, p-value < .001). During the first year after transplantation, these hazard ratios were 1.32 (1.06-1.64 95% CI, p-value .014) and .59 (.48-.73 95% CI, p-value < .001), respectively. Conclusions: CMV seropositivity is associated with an increased risk of graft loss in pediatric heart transplant recipients, which occurs early after transplantation and may be mitigated by antiviral therapy.

The Diagnostic Role of Echocardiographic Strain Analysis in Patients Presenting with Chest Pain and Elevated Troponin: A Multicenter Study.

BACKGROUND: Myocarditis presenting as acute chest pain with elevated troponins without significant cardiac compromise is rare in previously healthy children, often referred to as myopericarditis. Diagnosis is challenging, as conventional echocardiographic measures of systolic function can be normal. The aim of this study was to demonstrate the diagnostic utility of strain imaging in this scenario. METHODS: This was a multicenter, retrospective study including patients presenting with chest pain and elevated troponin from 10 institutions who underwent cardiac magnetic resonance imaging and transthoracic echocardiography within 30 days of each other (group 1). Findings were compared with those among 19 control subjects (group 2). Clinical data and conventional echocardiographic and cardiac magnetic resonance imaging data were collected. Echocardiography-derived strain was measured at the core laboratory. Group 1 was divided into subgroups as myocarditis positive (group 1a) or negative (group 1b) on cardiac magnetic resonance imaging on the basis of established criteria. RESULTS: Group 1 included 108 subjects (88 in group 1a, 20 in group 1b). Although all groups had normal mean fractional shortening and mean left ventricular ejection fraction, group 1 had significantly lower ejection fraction (56.8 ± 7.0%) compared with group 2 (62.3 ± 4.9%; P < .005) and fractional shortening (31.2 ± 4.9%) compared with group 2 (34.1 ± 3.5%; P < .05). Additionally, peak global longitudinal strain (GLS) was markedly abnormal in group 1 (-13.9 ± 3.4%) compared with group 2 (-19.8 ± 2.1%; P < .001). In subgroup analysis, GLS was markedly abnormal in group 1a (-13.2 ± 3.0%) compared with group 1b (-17.3 ± 2.6%; P < .001). Fifty-four subjects underwent follow-up echocardiography (46 in group 1a, eight in group 1b), with mean a follow-up time of 10 ± 11 months. At follow-up, whereas ejection fraction and fractional shortening returned to normal in all patients, abnormalities in strain persisted in group 1, with 22% still having abnormal GLS. Moreover, mean GLS was more abnormal in group 1a (-16.1 ± 2.6%) compared with group 1b (-17.4 ± 1.2%; P < .05). CONCLUSIONS: The present study demonstrates that echocardiographic GLS is significantly worse in subjects with myopericarditis presenting with chest pain and elevated troponins compared with control subjects even when conventional measures of systolic function are largely normal and that these abnormalities persisted over time.

Estimating filling pressures in paediatric heart transplant recipients using echocardiographic parameters and B-type natriuretic peptide.

BACKGROUND: Longitudinal evaluation of allograft diastolic function in paediatric heart transplant recipients is important for early detection of acute rejection, cardiac allograft vasculopathy, and graft dysfunction. Mean diastolic right atrial and pulmonary capillary wedge pressures obtained at catheterisation are the reference standards for assessment. Echocardiography is non-invasive and more suitable for serial surveillance, but individual parameters have lacked accuracy. This study aimed to identify covariates of post-transplant mean right atrial and pulmonary capillary wedge pressures, including B-type natriuretic peptide and certain echocardiographic parameters. METHODS: A retrospective review of 143 scheduled cardiac catheterisations and echocardiograms from 56 paediatric recipients transplanted from 2007 to 2011 was performed. Samples with rejection were excluded. Univariate and multivariate linear regression models using backward selection were applied to a database consisting of B-type natriuretic peptide, haemodynamic, and echocardiographic data. RESULTS: Ln B-type natriuretic peptide, heart rate z-score, left ventricular end-diastolic dimension z-score, mitral E/e', and percent interventricular septal thickening in systole were independently associated with mean right atrial pressure. Ln B-type natriuretic peptide, heart rate z-score, left ventricular end-diastolic dimension z-score, left ventricular mass (observed/predicted), and mitral E/e' were independently associated with mean pulmonary capillary wedge pressure. Covariates of B-type natriuretic peptide included mean pulmonary artery and pulmonary capillary wedge pressures, height, haemoglobin, fractional shortening, percent interventricular septal thickening in systole, and pulmonary vascular resistance index. CONCLUSIONS: B-type natriuretic peptide and echocardiographic indices of diastolic function were independently related to post-transplant mean right atrial and pulmonary capillary wedge pressures in paediatric heart transplant recipients without rejection.

Human leukocyte antigen eplet mismatching is associated with increased risk of graft loss and rejection after pediatric heart transplant.

BACKGROUND: While mismatching between donor and recipient human leukocyte antigen (HLA) alleles has been associated with increased graft loss in pediatric heart recipients, it is actually the surface amino acid structures, termed eplets, which determine the antigenicity of each HLA molecule. We hypothesized that HLA eplet mismatch analysis is a better predictor of adverse outcomes after pediatric heart transplant than conventional allele mismatch comparison. METHODS: A retrospective review of the Pediatric Heart Transplant Society database identified pediatric heart recipients (<18 years at listing) with complete donor and recipient HLA typing (A, B, and DR). Imputed high-resolution HLA genotypes were entered into HLAMatchmaker software which then calculated the number of eplet mismatches between each donor-recipient pair. Multivariable Cox regression analysis was used to examine associations between allele or eplet mismatching and adverse outcomes. RESULTS: Compared to those with <20 HLA class I eplet mismatches, recipients with 20 or more HLA class I eplet mismatches had an increased risk of graft loss (HR 1.46 [1.01-2.12], p = .049). HLA class I eplet mismatching was also associated with rejection (>20 mismatches: HR 1.30 [1.03-1.65], p = .030), while HLA class II eplet mismatching was associated with specified antibody-mediated rejection (10-20 mismatches: HR 1.57 [1.06-2.34], p = .025; >20 mismatches: HR 3.14 [1.72-5.71], p < .001). Neither HLA class I nor class II allele mismatching was significantly associated with graft loss or rejection. CONCLUSION: Eplet mismatch analysis was more predictive of adverse post-transplant outcomes (including graft loss and rejection) than allele mismatch comparison. Further study, including prospective high-resolution HLA typing, is warranted.

Clinical and hemodynamic characteristics of the pediatric failing Fontan.

AIM: To describe the clinical and hemodynamic characteristics of Fontan failure in children listed for heart transplant. METHODS: In a nested study of the Pediatric Heart Transplant Society, 16 centers contributed information on Fontan patients listed for heart transplant between 2005and 2013. Patients were classified into four mutually exclusive phenotypes: Fontan with abnormal lymphatics (FAL), Fontan with reduced systolic function (FRF), Fontan with preserved systolic function (FPF), and Fontan with "normal" hearts (FNH). Primary outcome was waitlist and post-transplant mortality. RESULTS: 177 children listed for transplant were followed over a median 13 (IQR 4-31) months, 84 (47%) were FAL, 57 (32%) FRF, 22 (12%) FNH, and 14 (8%) FPF. Hemodynamic characteristics differed between the 4 groups: Fontan pressure (FP) was most elevated with FPF (median 22, IQR 18-23, mmHg) and lowest with FAL (16, 14-20, mmHg); cardiac index (CI) was lowest with FRF (2.8, 2.3-3.4, L/min/m2). In the entire cohort, 66% had FP >15 mmHg, 21% had FP >20 mmHg, and 10% had CI <2.2 L/min/m2. FRF had the highest risk of waitlist mortality (21%) and FNH had the highest risk of post-transplant mortality (36%). CONCLUSIONS: Elevated Fontan pressure is more common than low cardiac output in pediatric failing Fontan patients listed for transplant. Subtle hemodynamic differences exist between the various phenotypes of pediatric Fontan failure. Waitlist and post-transplant mortality risks differ by phenotype.

An ethical analysis of obesity as a determinant of pediatric heart transplant candidacy.

BACKGROUND: Inclusion of BMI as criterion in the determination of heart transplant candidacy in children is a clinical and ethical challenge. Childhood obesity is increasing and children with heart disease are not spared. Currently, many adult heart transplant centers consider class II obesity and higher (BMI > 35 kg/m2 ) to be a relative contraindication for transplantation due to risk of poor outcome after transplant. No national guidelines exist regarding consideration of BMI in pediatric heart transplant and outcomes data are limited. This leaves decisions about transplant candidacy in obese pediatric patients to individual institutions or on a case-by-case basis, allowing for bias and inequity. METHODS: We review (a) the prevalence of childhood obesity, including among heart transplant candidates, (b) the lack of existing BMI guidelines, and (c) relevant literature on BMI and pediatric heart transplant outcomes. We discuss the ethical considerations of using obesity as a criterion using the principles of utility, justice, and respect for persons. RESULTS: Existing transplant outcomes data do not show that obese children have different or poor enough outcomes compared to non-obese children to warrant exclusion. Moreover, obesity in the United States is unequally distributed by race and socioeconomic status. Children already suffering from health disparities are therefore doubly penalized if obesity denies them access to life-saving transplant. CONCLUSION: Insufficient data exist to support using any BMI cutoff as an absolute contraindication for heart transplant in children. Attention should be paid to health equity issues when considering excluding a patient for transplant based on obesity.

Sleep-disordered breathing in pediatric heart transplant recipients.

BACKGROUND: Sleep-disordered breathing is commonly found in adults with heart failure both before and after HTx. Untreated sleep-disordered breathing post-transplant has been linked to late graft dysfunction, reduced quality of life, and increased morbidity. Sleep-disordered breathing has not been investigated in pediatric HTx recipients. METHODS: We conducted retrospective review of patients <21yo who underwent primary HTx at our center from 2009 to 2019 to describe clinical characteristics, cardiac history, and PSG results. RESULTS: One hundred and fifty patients were included; 60% had congenital heart disease, and 40% had cardiomyopathy. Fifty patients had PSG performed at median age of 6.1 years. Forty-one were referred for symptoms of sleep-disordered breathing. Obstructive sleep apnea was diagnosed in 45 patients and central sleep apnea in 3 patients. Of those with first PSG post-transplant (n = 36), median AHI was 9.1/h, and 19 (53%) were diagnosed with moderate or severe sleep apnea. Patients diagnosed with obstructive sleep apnea on PSG had more post-transplant ventilator days (median 3 vs 2 days, P < .05) and longer post-transplant lengths of stay (median 28 vs 22 days, P < .05). CONCLUSIONS: In this single-center cohort of pediatric HTx recipients, sleep-disordered breathing was common and associated with longer peri-transplant respiratory support and length of stay. Given the high incidence of moderate and severe OSA detected in this population, clinicians should regularly screen for SDB and consider PSG testing more frequently in children who have undergone HTx. Further study into the long-term impact of sleep-disordered breathing in pediatric HTx recipients is needed.

Assessment of rejection risk following subtherapeutic calcineurin inhibitor levels after pediatric heart transplantation.

CNIs are the mainstay of immunosuppressive therapy after pediatric HTx. While regular laboratory surveillance is performed to ensure blood levels are within targeted range, the risk of acute rejection associated with subtherapeutic CNI levels has never been quantified. This is a retrospective single-center review of 8413 CNI trough levels in 138 pediatric HTx recipients who survived >1 year after HTx. Subtherapeutic CNI levels were defined as <50% of the lower limit of target range. The risk of acute, late (>12 months post-transplant) rejection following recipients' subtherapeutic CNI levels was assessed using time-varying multivariable Cox proportional hazards analysis. We found that 79 of 138 recipients (57%) had at least one subtherapeutic CNI level on routine surveillance laboratories during a mean follow-up of 5.5 ± 3.6 years. Following an episode of subtherapeutic levels, 17 recipients (22%) had biopsy-proven rejection within the next 3 months; the majority (9/17) within the first 2 weeks. After presenting with subtherapeutic CNI levels, recipients incurred a 6.1 times increased risk of acute rejection in the following 3 months (HR = 6.11 [2.41, 15.51], P = <.001). Age at HTx, HLA sensitization, or positive crossmatch were not associated with acute late rejection, but rejection in the first post-transplant year was (HR 2.61 [1.27, 5.35], P = .009). Thus, maintaining therapeutic CNI levels is the most important factor in preventing acute rejection in recipients who are >12 months after pediatric HTx. Recipients who present with subtherapeutic CNI levels on surveillance monitoring are 6.1 times more likely to develop rejection in the following 3 months.

A fatal case of bortezomib-induced lung toxicity in a young adult heart transplant recipient.

Bortezomib is approved for the treatment of multiple myeloma but increasingly used in heart transplant (HTx) recipients with antibody-mediated rejection (AMR). Severe pulmonary toxicity is a rare complication in multiple myeloma patients treated with bortezomib, but has not been described in a solid organ transplant recipient. A 20-year-old man 7 years post-HTx presented with acute rejection with hemodynamic compromise. Endomyocardial biopsy showed mixed rejection (ISHLT grade 2R-3R acute cellular rejection (ACR) and pAMR 1 (I+) with diffuse C4d staining). Two new high MFI circulating MHC class-II donor-specific antibodies (DSA) were detected. Treatment included corticosteroids, antithymocyte globulin, plasmapheresis, IVIG, rituximab, and bortezomib (1.3 mg/m2 ). Due to rebound in DSA, a second course of bortezomib was started. Thrombocytopenia and peripheral neuropathy prompted a 50% dose reduction during the 2nd course. Shortly after the 3rd reduced dose, the patient developed hypoxemic respiratory failure. Bronchoscopy revealed pulmonary hemorrhage with negative infectious studies. Chest CT showed bilateral parenchymal disease with bronchiectasis and alveolar bleeding. Despite treatment with high-dose steroids, severe ARDS ensued with multisystem organ failure. The patient expired 23 days after the final dose of bortezomib. Post-mortem lung histology revealed diffuse alveolar damage, pulmonary fibrosis, and hemorrhage. Cardiac histology showed resolving/residual ACR 1R and pAMR 1 (I+). While rare, bortezomib-induced lung toxicity (BILT) can occur in HTx recipients and can carry a high risk of mortality. Drug reaction and immediate drug withdrawal should be considered in patients who develop respiratory symptoms, though optimal management of BILT is unclear.

Management of the sensitized pediatric heart transplant patient.

Despite advancements in transplant immunosuppression and techniques for managing critically ill patients awaiting heart transplantation, children who are immunologically sensitized to human leukocyte antigen remain at increased risk for morbidity and mortality, both while awaiting and after heart transplant. In this review we will discuss the epidemiology of sensitization, review the immunologic basis and methods of human leukocyte antigen antibody detection, describe outcomes for sensitized pediatric transplant candidates, and consider both pre- and post-transplant management options for sensitized patients.