Heart Transplantation for Pediatric and Congenital Cardiac Disease: A Comparison of Two Eras over 23 Years and 188 Transplants at a Single Institution.

BACKGROUND: To assess changes in patterns of practice and outcomes over time, we reviewed all patients who underwent heart transplantation (HTx) at our institution and compared two consecutive eras with significantly different immunosuppressive protocols (cohort 1 [80 HTx, June 1995-June 2006]; cohort 2 [108 HTx, July 2006-September 2018]). METHODS: Retrospective study of 180 patients undergoing 188 HTx (June 1995-September 2018; 176 first time HTx, 10 second HTx, and 2 third HTx). In 2006, we commenced pre-HTx desensitization for highly sensitized patients and started using tacrolimus as our primary postoperative immunosuppressive agent. The primary outcome was mortality. Survival was modeled by the Kaplan-Meier method. Univariable and multivariable Cox proportional hazard models were created to identify prognostic factors for survival. RESULTS: Our 188 HTx included 18 neonates, 85 infants, 83 children, and 2 adults (>18 years). Median age was 260.0 days (range: 5 days-23.8 years). Median weight was 7.5 kg (range: 2.2-113 kg). Patients in cohort 1 were less likely to have been immunosensitized preoperatively (12.5% vs 28.7%, P = .017). Nevertheless, Kaplan-Meier analysis suggested superior survival in cohort 2 (P = .0045). Patients in cohort 2 were more likely to be alive one year, five years, and ten years after HTx. Multivariable analysis identified the earlier era (hazard ratio [HR] [95% confidence interval] for recent era = 0.32 [0.14-0.73]), transplantation after prior Norwood operation (HR = 4.44 [1.46-13.46]), and number of prior cardiac operations (HR = 1.33 [1.03-1.71]) as risk factors for mortality. CONCLUSIONS: Our analysis of 23 years of pediatric and congenital HTx reveals superior survival in the most recent 12-year era, despite the higher proportion of patients with elevated panel reactive antibody in the most recent era. This improvement was temporally associated with changes in our immunosuppressive strategy.

Hyaluronidase-Facilitated High-Dose Subcutaneous IgG Effectively Controls Parvovirus B19 Infection in a Pediatric Cardiac Transplant Patient With Severe T-Cell Lymphopenia.

We treated three pediatric cardiac transplant patients with chronic parvovirus viremia with high-dose intravenous immunoglobulin (HD-IVIG). One patient with severe T-cell lymphopenia suffered recurrent viremia and aseptic meningitis, which resolved remarkably when he was switched to high-dose hyaluronidase-facilitated subcutaneous immunoglobulin (HD-SCIG-Hy). We discuss the advantages of HD-SCIG-Hy vs HD-IVIG treatment for similar cases.

Resource utilization of cytomegalovirus immune globulin in prevention and treatment of cytomegalovirus infection in pediatric heart transplantation.

BACKGROUND: There is debate whether cytomegalovirus immunoglobulin (CMV-Ig) is also needed for CMV prevention in heart transplant recipients in the era of good anti-viral drugs. METHODS: We conducted a cost-savings quality initiative on CMV-Ig eventually leading to discontinuation of routine use of CMV-Ig for CMV prevention. Subsequently, a retrospective cohort study was conducted, comparing patients in cohort I (CMV-Ig plus anti-viral drugs, 2013-2015) to cohort II (anti-virals alone, 2015-2017). The medication acquisition costs and outcomes of CMV infection were assessed. RESULTS: There were 39 total patients: 22/39(56%) in cohort I, with mean follow-up of 35.14 ± 17.38 months and 17/39(44%) in cohort II, mean follow-up of 19.12 ± 7.08 months. In cohort I, 5/22(22.7%) patients died from causes unrelated to CMV and 0/17 in cohort II died. There were 5/22(22.7%) patients in cohort I, and 2/17(9%) patients in cohort II that developed CMV infection (P = .508). Freedom from rejection was 81.8% (18/22) in cohort I, and 71% (12/17) in cohort II (P = .46), and 100% for allograft vasculopathy. There was significant reduction in medication acquisition cost following the protocol change of $260 839 or $15 343 per patient. CONCLUSION: Our study demonstrated an acquisition cost savings with similar clinical outcomes utilizing anti-viral CMV prophylaxis alone vs anti-viral prophylaxis plus CMV-Ig.

Risk Factors for Survival After Heart Transplantation in Children and Young Adults: A 22-Year Study of 179 Transplants.

BACKGROUND: This article reviews all patients who underwent heart transplantation (HTx) within a single institution (172 patients underwent 179 HTx [167 first-time HTxs, 10 second HTxs, 2 third HTxs]) to describe diagnostic characteristics, management protocols, and risk factors for mortality. METHODS: Descriptive analysis was performed for the entire cohort using mean, standard deviation, median, interquartile range, and overall range, as appropriate. Univariable and multivariable Cox proportional hazards models were performed to identify prognostic factors for outcomes over time. The primary outcome of interest was mortality, which was modeled by Kaplan-Meier analysis. RESULTS: Median age at HTx was 263 days (range, 5 days to 24 years; mean = 4.63 ± 5.95 years; 18 neonates, 79 infants). Median weight at HTx was 7.5 kg (range, 2.2-113 kg; mean = 19.36 ± 23.54). Diagnostic categories were cardiomyopathy (n = 62), primary transplantation for hypoplastic left heart syndrome (HLHS) or HLHS-related malformation (n = 33), transplantation after cardiac surgery for HLHS or HLHS-related malformation (n = 17), non-HLHS congenital heart disease (n = 55), and retransplant (n = 12). Operative mortality was 10.1% (18 patients). Cumulative total follow-up is 1,355 years. Late mortality was 18.4% (33 patients). Overall Kaplan-Meier five-year survival was 76.2%. One hundred twenty-one patients are alive with a mean follow-up of 7.61 ± 6.46 years. No survival differences were seen among the five diagnostic subgroups ( P = .064) or between immunosensitized patients (n = 31) and nonimmunosensitized patients (n = 141; P = .422). CONCLUSIONS: Excellent results are expected for children undergoing HTx with comparable results among diagnostic groups. Pretransplant mechanical circulatory support and posttransplant mechanical circulatory support are risk factors for decreased survival. Survival after transplantation for HLHS or HLHS-related malformation is better with primary HTx in comparison to HTx after prior cardiac surgery.

Case report and review of the literature: the utilisation of a ventricular assist device as bridge to recovery for anthracycline-induced ventricular dysfunction.

Ventricular assist devices are used in children with heart failure as a bridge to myocardial recovery or cardiac transplantation. Anthracyclines cause cardiac toxicity and may result in acute or long-term cardiac failure. We describe the use of a ventricular assist device as a bridge to recovery in a child with severe acute anthracycline-induced cardiomyopathy, and we review the associated literature. A 6-year-old girl was treated for acute myeloblastic leukaemia with daunorubicin and mitoxantrone. After 2 weeks her final dose of chemotherapy, her Left Ventricular Ejection Fraction decreased to 21%. Despite initiation of medical therapy, she had continued deterioration of left ventricular function and developed evidence of poor end-organ perfusion. She was not a candidate for cardiac transplantation, as the post-transplant immune suppression therapy would put her at risk for recurrence of her malignancy. We placed her on a short-term ventricular assist device as a bridge to ultimately placing her on a long-term ventricular assist device versus continuing medical therapy. Her left ventricular ejection fraction improved to 55% 24 days after ventricular assist device insertion. She was separated from the ventricular assist device 26 days after its insertion. She was discharged home 29 days later and is now 28 months after ventricular assist device implantation with stable ventricular function, as documented by a left ventricular ejection fraction of 55%, and normal end organ function. This case is one of the only reports known describing successful use of a short-term ventricular assist device as a bridge to recovery in a child with severe acute anthracycline-induced cardiotoxicity.

Conversion from calcineurin inhibitors to mTOR inhibitors as primary immunosuppressive drugs in pediatric heart transplantation.

There are only a few reports of successful use of mammalian target of rapamycin (mTORI) as primary immunosuppression in pediatric heart transplantation. Compared to calcineurin inhibitors, mTORI have less side effects, especially nephrotoxicity, infections, and malignancies. A retrospective study was conducted at our institution of all 170 heart transplants from 1995 to 2015. Nineteen patients were switched from tacrolimus (n=15) or cyclosporin (n=4) to everolimus (n=4) or sirolimus (n=15) due to nephrotoxicity (n=5), malignancy (n=8), EBV viremia/reactive plasmacytic changes (n=5), and immune hemolytic anemia (n=1). We monitored for rejection, infection, BUN, creatinine, hyperlipidemia, EBV and CMV copies, CBC, cardiac allograft vasculopathy (CAV), and death. Target trough levels of sirolimus and everolimus were 4-10. Four treatment failures included debilitating rash, bone marrow suppression, recurrent rejection, and renal transplantation. There were no deaths. One patient had recurrent rejection episodes, and tacrolimus was reinitiated. One patient with preexisting CAV underwent heart retransplantation. One patient, who was treated for PTLD, transformed to CD30+ Hodgkins disease, and was treated with brentuximab. There were three acute rejection episodes. Median creatinine preswitch was higher 0.82 than postswitch 0.78 (P=.016). Median eGFR was lower preswitch, 75.6, than postswitch, 91.2 (P=.0004). These results indicate that conversion to mTORI as primary immunosuppression may be safely accomplished in some pediatric heart transplant patients.

Outcomes in highly sensitized pediatric heart transplant patients using current management strategies.

BACKGROUND: Previous studies have suggested that children with pre-formed anti-HLA antibodies (PRA) undergoing orthotopic heart transplantation (OHT) have increased risk for rejection, coronary artery vasculopathy (CAV) and death. In 2005, our program started utilizing aggressive desensitization (including plasmapheresis, IVIg, pulse cytoxan and rituximab) with the goal of improving outcomes for these patients. The purpose of this study was to compare outcomes with this new strategy in recipients with pre-OHT high PRA (>10%) vs low PRA ≤10%). METHODS: A retrospective study of 70 consecutive pediatric OHT patients was undertaken between January 2005 and July 2013 to identify patients with pre-OHT PRA >10% (high PRA), or PRA ≤10% (low PRA). Demographic/data information and detailed post-OHT outcomes, including rejection, 30-day and overall mortality, freedom from significant rejection, and CAV, were analyzed. RESULTS: Fourteen (20%) patients had high PRA and 56 (80%) did not. There was a significant decrease in PRA values before and after desensitization. Thirty-day and overall mortality and the proportion of patients with rejections or CAV were lower in the high PRA group, although the difference was not statistically significant. Kaplan-Meier survival analysis revealed no significant difference in survival between the two groups. There was a significant difference in survival in our sensitized patients before 2005 vs after 2005. CONCLUSIONS: We identified no significant differences in outcomes between high or low PRA patients. These preliminary findings may suggest improvement in OHT outcomes for high PRA patients as a result of aggressive desensitization. A larger study is warranted to confirm these findings.