Jacob Simmonds

Heart transplantation after congenital heart surgery: improving results and future goals.

With growing numbers of children with complex congenital heart disease surviving initial surgical procedures, more patients are presenting in later childhood or early adulthood in cardiac failure. This presents an obvious increased burden on transplant centres, and a further strain on a limited donor pool. Historically, results for heart transplant following congenital heart disease (CHD) have been worse than those following cardiomyopathy. With increased surgical experience and intensive care expertise, the gap between the two aetiologies in our practice is decreasing. This article reviews the current protocols for transplantation in this setting, presenting a large single-centre experience over 20 years, and speculates on possible future advancements in this very challenging field.

Endothelial Dysfunction and Cytomegalovirus Replication in Pediatric Heart Transplantation

Background— Cardiac allograft vasculopathy is the major limiting factor to the long-term success of pediatric heart transplantation. Cytomegalovirus (CMV) has been shown to be a significant risk factor for the development of cardiac allograft vasculopathy. Recent work has demonstrated CMV DNA in leukocytes in the absence of direct allograft infection, suggesting that vascular changes may not be limited to the allograft. Method and Results— Systemic arterial endothelial function was assessed with high-resolution ultrasound to determine brachial artery flow-mediated dilation in 50 pediatric heart transplant recipients (8 to 17 years of age; 27 male). Patients were separated into 2 groups according to CMV status: those without evidence of CMV replication after transplantation (n=38; 19 male) and patients with evidence of viremia after transplantation (n=12; 8 male). No patient had detectable viremia at the time of study. Flow-mediated dilation was significantly impaired in patients with evidence of CMV replication after transplantation (6.64±1.12%, mean±SE) compared with those without (9.48±0.56%; P=0.02). This difference remained after adjustment for age, time since transplantation, and medication. Pretransplantation recipient and donor CMV status and traditional CMV risk were not associated with flow-mediated dilation. Conclusions— CMV replication after cardiac transplantation is associated with chronic endothelial dysfunction in the systemic circulation in children. The implication for both systemic and coronary vascular health requires prospective evaluation.

Pre-implantation basiliximab reduces incidence of early acute rejection in pediatric heart transplantation.

BACKGROUND Basiliximab is an anti-CD25 monoclonal antibody used as induction therapy in solid-organ transplantation. In this study we aim to determine whether pre-operative administration of basiliximab is beneficial in preventing early heart allograft rejection. METHODS In this investigation we assess the effect of pre-implantation basiliximab on CD25 count and on acute rejection in children undergoing cardiothoracic transplantation. The notes of all children undergoing cardiothoracic transplantation at the Great Ormond Street Hospital between January 2000 and June 2007 were retrospectively reviewed. One hundred twenty-one heart transplant recipients were included: 29 patients did not receive basiliximab; 33 patients received basiliximab after coming off cardiopulmonary bypass (CPB); and 59 patients received basiliximab prior to organ implantation. RESULTS All patients receiving basiliximab had an effectively suppressed CD25 count (<0.2%) on Days 1 and 10 post-transplant. Freedom from Grade 3A or greater rejection in the first year was significantly greater in the pre-implantation basiliximab group than in the post-implantation and no-basiliximab groups (95%, 70% and 72%, respectively; p = 0.02). Induction regimen was the only significant explanatory variable after multivariate Cox regression. CONCLUSIONS The results of this study confirm that basiliximab is effective at suppressing CD25 count whether given pre- or post-CPB. Basiliximab before transplantation appeared to reduce acute rejection, whereas post-CPB administration did not suggest similar effects. These findings require independent validation in randomized trials and further studies should seek to mechanistically delineate these observations.

Long-term steroid treatment and growth: a study in steroid-dependent nephrotic syndrome.

Objective High-dose steroid therapy in children is known to impair growth. What is unknown is the level of steroid therapy at which children continue to grow normally. This study was designed to deduce a dosage of prednisolone compatible with normal growth. Patients and design The growth of 41 children (age 1.92–13.2 years) with steroid-dependent nephrotic syndrome (SDNS) was studied using recordings from clinic visits over the course of their follow-up at Great Ormond Street Hospital (study period range 1.38–8.43 years, mean 4.2 years, total 172 years). The height standard deviation score (SDS) and the SDS velocity between clinics were calculated, and compared to the contemporary dose of prednisolone (converted to an equivalent daily dose when on an alternate day regime). Results The mean dose of prednisolone was 0.44 mg/ kg/day (range 0.06–1.45 mg/kg/day). The mean change in height SDS velocity over the course of recording was −0.02 SDS/year (boys −0.14 SDS/year, girls +0.16 SDS/year). Overall, there was no negative effect on growth seen at doses of prednisolone of less than 0.75 mg/kg/day. At doses higher than 0.75 mg/kg/day, there was a small decline in height SDS velocity (−0.14 SDS/ year). Conclusions Overall, prednisolone treatment in these children was not shown to adversely affect their height SDS. This was true even at doses of prednisolone up to 0.5–0.75 mg/kg/day. There was some decline in height SDS seen during periods of higher steroid use (over 0.75 mg/kg/day), but periods on lower doses allowed for adequate catch up growth.

Tacrolimus in pediatric heart transplantation: ameliorated side effects in the steroid‐free, statin era

Abstract:  Due to concerns over the side effects of cyclosporine, tacrolimus is widely used in pediatric heart transplantation. However, tacrolimus therapy is also accompanied by potentially serious side effects. This paper examines the side effect profile of tacrolimus in a large group of pediatric heart recipients. Data on renal function, diabetes, hyperlipidemia and hypertension were collected by case‐note review of 100 patients who had received ≥ 12 months treatment with tacrolimus. Forty‐two patients received tacrolimus from the time of transplant (de novo), and 58 were initially treated with cyclosporine (switch). Mean estimated glomerular filtration rate improved in the first six months post transplant in the de novo group (66.7–84.6 mL/min/1.73 m2, p = 0.002). Conversely, it decreased in those initially treated with cyclosporine (82.1–68.8, p = 0.032), but improved after switch to tacrolimus (77.3–85.6, p = 0.006). Twenty‐one percent exhibited glucose intolerance, and 2% had diabetes. Borderline or elevated fasting cholesterol levels were present in 4.4%. Hypertension was seen in 67% at the point of switch from cyclosporine, which fell to 36% at latest follow‐up (p = 0.001). These results present an encouraging outlook for this cohort of patients. The relatively low levels of complications shown may be due to early weaning of steroids, and concomitant statin therapy.

Neither age at repair nor previous palliation affects outcome in tetralogy of Fallot repair

OBJECTIVES The study aimed to evaluate the results following complete repair of tetralogy of Fallot (TOF) in relation to age at surgery and to assess the role of palliation in the current era. METHODS A retrospective review of 251 consecutive patients with TOF repaired between 2003 and 2011 at the Great Ormond Street Hospital was performed. Children were divided into two groups: Group A, younger than 6 months (n = 78) and B, older than 6 months (n = 173). Early clinical outcomes and reoperation/reintervention rates were studied as well as indication for a palliation. RESULTS There was 1 (0.4%) early and 1 (0.4%) late death after a median follow-up time of 4.5 years. Forty-three patients (17%) underwent repair after initial palliation with inter-stage mortality of 5%. Groups A and B were similar in terms of surgical approach, postoperative complications and length of stay. Significant differences were found in terms of more frequent use of a transannular patch (P = 0.05), longer surgeries (P = 0.02) and a greater proportion of palliated patients (P = 0.002) in older patients. There was no difference in rates of reoperation/reintervention between groups and following both primary and staged repair. Palliated patients were more symptomatic (duct-dependent pulmonary blood flow; P < 0.01, cyanotic spells; P < 0.01), had more extracardiac/genetic anomalies (P < 0.01), coronary anomalies (P = 0.015) and significantly smaller pulmonary annulus, right pulmonary artery (RPA) and left pulmonary artery (LPA) Z-scores (P < 0.01 for all). CONCLUSION Age at complete repair was not linked to early clinical outcome or reoperation/reintervention rate. Palliative procedures postponed the timing of complete repair, but did not increase the reintervention rate.

Total donor ischemic time: Relationship to early hemodynamics and intensive care morbidity in pediatric cardiac transplant recipients*

Objective: Single-center studies have failed to link modest increases in total donor ischemic time to mortality after pediatric orthotopic heart transplant. We aimed to investigate whether prolonged total donor ischemic time is linked to pediatric intensive care morbidity after orthotopic heart transplant. Design: Retrospective cohort review. Setting: Tertiary pediatric transplant center in the United Kingdom. Patients: Ninety-three pediatric orthotopic heart transplants between 2002 and 2006. Methods: Total donor ischemic time was investigated for association with early post-orthotopic heart transplant hemodynamics and intensive care unit morbidities. Results: Of 43 males and 50 females with median age 7.2 (interquartile range 2.2, 13.0) yrs, 62 (68%) had dilated cardiomyopathy, 20 (22%) had congenital heart disease, and nine (10%) had restrictive cardiomyopathy. The mean total donor ischemic time was 225.9 (sd 65.6) mins. In the first 24 hrs after orthotopic heart transplant, age-adjusted mean arterial blood pressure increased (p < .001), mean pulmonary arterial pressure fell (p = .012), but central venous pressure (p = .58) and left atrial pressure (p = .20) were unchanged. After adjustment for age, primary diagnosis, pre-orthotopic heart transplant mechanical support, and marginal donor factors, longer total donor ischemic time was significantly associated with lower mean arterial blood pressure (p < .001) in the first 24 hrs after orthotopic heart transplant, longer post-orthotopic heart transplant mechanical ventilation (p = .03), longer post-orthotopic heart transplant stay in the intensive care unit (p = .004), and longer post-orthotopic heart transplant stay in hospital (p = .02). Total donor ischemic time was not related to levels of mean pulmonary arterial pressure (p = .62), left atrial pressure (p = .38), or central venous pressure (p = .76) early after orthotopic heart transplant. Conclusions: Prolonged total donor ischemic time has an adverse effect on the donor organ, contributing to lower mean arterial blood pressure, as well as more prolonged ventilation and intensive care unit and hospital stays post-orthotopic heart transplant, reflecting increased morbidity.

Successful heart transplantation following neonatal necrotic enterovirus myocarditis.

Enterovirus myocarditis is a potentially devastating diagnosis in the neonatal setting, with an associated high mortality and risk for chronically impaired cardiac function. Transplantation may be a possible therapeutic option, but, due to the comparative scarcity of the presentation, the limited donor pool, and fears of viral persistence and recurrence of myocarditis (especially in the immunocompromised, post-transplant setting), there are no reported cases in the literature. This case report illustrates an encouraging one-year outcome following heart transplantation for necrotic enterovirus myocarditis in a neonate.

Inflammatory Cytokines, Endothelial Function, and Chronic Allograft Vasculopathy in Children: An Investigation of the Donor and Recipient Vasculature After Heart Transplantation.

Chronic allograft vasculopathy (CAV) limits the lifespan of pediatric heart transplant recipients. We investigated blood markers of inflammation, endothelial dysfunction, and damage to both the native and transplanted vasculature in children after heart transplantation. Serum samples were taken from pediatric heart transplant recipients for markers of inflammation and endothelial activation. The systemic vasculature was investigated using brachial artery flow‐mediated dilatation and carotid artery intima‐medial hyperplasia. CAV was investigated using intravascular ultrasound. Mean intima‐media thickness (mIMT) > 0.5 mm was used to define significant CAV. Forty‐eight children (25 male) aged 8–18 years were enrolled in the study. Patients were a median (interquartile range) 4.1 (2.2–8.7) years after transplant. Patients had increased levels of circulating IL6 (3.86 [2.84–4.95] vs. 1.66 [1.22–2.63] p < 0.0001), vascular cell adhesion molecule 1 (539 [451–621] vs. 402 [342–487] p < 0.001), intracellular adhesion molecule 1 305 (247–346) vs. 256 (224–294) p = 0.002 and thrombomodulin (7.1 [5.5–8.1] vs. 3.57 [3.03–4.71] p < 0.0001) and decreased levels of tumor necrosis factor‐α, E selectin, and P selectin, compared with controls. The systemic vasculature was unaffected. Patients with severe CAV had raised serum von Willebrand factor and decreased serum thrombomodulin. Posttransplant thrombomodulin levels are elevated after transplant but significantly lower in those with mIMT > 0.5 mm. This suggests that subclinical inflammation is present and that natural anticoagulant/thrombomodulin activity is important after transplant.

Rapid emergence of HCMV drug resistance in immunocompromised paediatric patients detected using target enrichment and deep sequencing

Background Cytomegalovirus can cause fatal disease in immunocompromised patients. With the advent of new anti-HCMV drugs there is interest in using virus sequence data to monitor resistance and identify new mutations. Methods We used target-enrichment to deep sequence HCMV DNA from 11 immunosuppressed paediatric patients receiving single or combination anti-HCMV treatment, serially sampled over 1-27 weeks. Changes in consensus sequence and resistance mutations were analysed for three ORFs targeted by anti-HCMV drugs and the frequencies of drug resistance mutations monitored. Results Targeted-enriched sequencing of clinical material detected mutations occurring at frequencies of 2%. Seven patients showed no evidence of drug resistance mutations. Four patients developed drug resistance mutations a mean of 16 weeks after starting treatment. In two patients, multiple resistance mutations accumulated at frequencies of 20% or less, including putative resistance mutations P522Q (UL54) and C480F (UL97). In one patient, resistance was detected 14 days earlier than by PCR. Phylogenetic analysis suggested recombination or superinfection in one patient. Conclusions Deep sequencing of HCMV enriched from clinical samples excluded resistance in 7 of eleven subjects and identified resistance mutations earlier than conventional PCR-based resistance testing in 2 patients. Detection of multiple low level resistance mutations was associated with poor outcome.