Pediatric Cardiac Transplant Recipients Research Articles

Prognostic Value of Exercise Stress Echocardiography in Pediatric Cardiac Transplant Recipients

Cardiac allograft vasculopathy (CAV) is a leading cause of long-term morbidity and mortality in pediatric heart transplant (HTx) recipients. Exercise stress echocardiography (ESE) has been shown to be useful in the detection of angiographically confirmed coronary artery disease in children. However, the prognostic utility of ESE for prediction of cardiac events in HTx survivors is unknown. We aim to assess whether an abnormal (positive) ESE is be associated with a higher risk of future cardiovascular (CV) outcomes in pediatric HTx recipients. We conducted a retrospective review of CV outcomes in a cohort of 95 pediatric HTx recipients who underwent 188 ESEs over a 10-year period. A composite endpoint for CV events including myocardial infarction, hospitalization for nonrejection heart failure, coronary revascularization, need for repeat transplantation, and death was used. Based on the interpretation of the ESE results, each ESE study was classified for this study as either positive (abnormal) or negative (normal) for ischemia. Results of the coronary angiograms performed near the time of ESE were also assessed and classified for this study as positive (abnormal) or negative (normal) for CAV according to standard HTx criteria for CAV. Fifty-one (27%) ESEs were positive for ischemia. There was a total of 35 CV events in 23 patients. A positive ESE was associated with increased risk of any CV event (hazard ratio=3.55; 95% CI, 1.52, 8.28), as well as an increased risk of CV death (hazard ratio=3.19; 95% CI, 1.23, 8.28). Freedom from composite CV outcome at 1, 2, and 3years following a positive ESE was 89.9% (95% CI=77.3%, 95.7%), 81.5% (95% CI=65.9%, 90.5%), and 63.2% (95% CI=41.9%, 78.5%), respectively. Freedom from composite CV outcome at 1, 2, and 3years following a negative ESE was 99.3% (94.8, 99.9), 98.4% (93.6, 99.6), and 97.0% (90.6, 99.1), respectively. No patient died within 1year of a negative ESE. In this largest study of ESE in pediatric HTx recipients, a positive or abnormal ESE is associated with increased future CV morbidity and mortality. Conversely, a negative ESE can help predict CV event-free survival. Even in the setting of a normal coronary angiogram, our pilot data show that an abnormal ESE may still be clinically important. Use of ESE in follow-up may improve risk stratification and management of pediatric HTx recipients.

Racial and Ethnic Disparities in Incidence and Prognosis of Perioperative Stroke Among Pediatric Cardiac Transplant Recipients.

Background In the general population, Black children have a higher incidence of stroke and all-cause mortality after stroke than White children. Beginning 6 months following cardiac transplantation, Black children have higher mortality than White children. However, whether there are racial and ethnic disparities in incidence and all-cause mortality following perioperative stroke among pediatric cardiac transplant recipients is unknown. Methods and Results Using the Scientific Registry of Transplant Recipients, we studied children who underwent their first heart transplant in the United States between January 1994 and September 2019. Using multivariable logistic regression, we assessed the association between race and ethnicity and perioperative stroke. We used multivariable piecewise Cox regression to examine the association between race and ethnicity and mortality among survivors of perioperative stroke. Among 8224 children who had a first cardiac transplant, 255 (3%) had a perioperative stroke. Black children had 32% lower odds of perioperative stroke compared with White children (adjusted odds ratio, 0.68 [95% CI, 0.46-0.996]). Following perioperative stroke, mortality rates were similar for Black and White children in the first 6months (adjusted hazard ratio [HR], 0.99 [95% CI, 0.44-2.26]). However, Black children had a higher mortality rate than White children beyond 6 months (adjusted HR, 3.36 [95% CI, 1.22-9.22]). Conclusions Among pediatric cardiac transplant recipients, Black children have a lower incidence of perioperative stroke than White children. Among survivors of perioperative stroke, mortality is initially similar by race and ethnicity, but beyond 6 months, Black children have over a 3-fold higher mortality rate than White children. Identifying and intervening on potential differences in care is essential to addressing these disparities.

Abstract WP172: Racial Disparities In Perioperative Stroke And Mortality Following Stroke Among Pediatric Cardiac Transplant Recipients

Introduction: In the general population, Black children have a higher incidence of stroke and all-cause mortality after stroke. Following cardiac transplantation, mortality is similar across Black and white children within the first 6 months, but Black children have higher mortality beyond 6 months. However, whether there are racial disparities in incidence and all-cause mortality following perioperative stroke among pediatric cardiac transplant recipients is unknown. Methods: Using the Scientific Registry of Transplant Recipients, we examined all children in the United States with their first heart transplant from January 1994-September 2019. We used multivariable logistic regression to assess the association between race and perioperative stroke. We used Kaplan Meier survival curves and multivariable piecewise Cox proportional hazard regression to examine the association between race and mortality among children who survived a perioperative stroke. Results: Among 8,224 children who had a first cardiac transplant, 255 (3%) had a perioperative stroke. Black children had a 32% lower odds of perioperative stroke compared to white children (OR=0.68, 95%CI 0.46-0.996). In unadjusted and multivariable-adjusted analyses, survival was similar for Black and white children in the first 6 months following perioperative stroke (Figure 1a, adjusted HR = 1.13, 95%CI 0.57-1.83), however Black children had a lower survival probability compared to white children beyond 6 months (Figure 1b, adjusted HR = 3.21, 95%CI 1.19-8.69, log-rank p=0.017). Conclusion: Among pediatric cardiac transplant recipients, Black children have a lower incidence of perioperative stroke than white children. Following perioperative stroke during cardiac transplantation, mortality is similar by race, but beyond 6 months, Black children have a higher mortality rate than white children. Intervening on potential differences in care is essential to addressing these disparities.

Expanded utilization of rituximab in paediatric cardiac transplant patients.

Epstein-Barr virus (EBV) viraemia and autoimmune cytopenias (AICs) are significant complications that occur following paediatric solid organ transplantation. A variety of treatment methods have been investigated but limited research has focused on the utilization of rituximab in paediatric cardiac transplant recipients for these indications. Rituximab is a monoclonal antibody that binds the CD20 antigen on the surface of B-type lymphocytes resulting in B-cell cytotoxicity. It is considered a second-line therapy for treatment of autoimmune cytopenias and EBV viraemia following adult solid organ transplant (SOT) and haematopoietic stem cell transplant (HSCT). However, data for its use in the paediatric population for treatment of autoimmune cytopenias are lacking. Dosing is based on adult studies, and the frequency and length of therapy associated with resolution of EVB viraemia and AICs in paediatric cardiac transplant recipients is unknown. The objective of this retrospective study was to describe the dosing and length of therapy of expanded off-label use of rituximab for the management of refractory EBV viraemia and AICs, specifically in paediatric cardiac transplant patients. A retrospective chart review was conducted evaluating children <18years of age who underwent cardiac transplantation, were diagnosed with EBV viraemia or autoimmune cytopenia, and subsequently received treatment with rituximab between June 1995 and October 2018. Data were analysed descriptively. Of all (n=188) paediatric cardiac transplant recipients since 1995, 10 patients met the inclusion/exclusion criteria. Primary diagnoses were EBV viraemia (n=6), immune haemolytic anaemia (n=3) and immune thrombocytopenic purpura (n=1). Complete responses were observed in 83.3% and 100% of patients with EVB viraemia and AICs treated with rituximab, respectively. All patients (n=10) received rituximab 325mg/m2 at weekly intervals. The number of total doses associated with complete resolution was 4-6 doses for EBV viraemia and 2-4 doses for AICs. The most common adverse events reported were neutropenia (n=3), thrombocytopenia (n=4), infusion reactions (n=1) and significant anaemia (n=2). Although the efficacy of rituximab for treatment of EBV viraemia and autoimmune cytopenia in the paediatric cardiac transplant population remains unclear, our study supported the benefit of rituximab when added to therapy for treatment of EBV viraemia and ACIs.

Simultaneous Assessment of Plasma and Peripheral Mononuclear Cells for Multiple Viral Load Quantification in Peripheral Blood of Patients after Heart Transplantation

Purpose Epstein-Barr Virus (EBV) is well known to be associated with posttransplant lymphoproliferative disorders (PTLD). Due to moderate immunosuppression in heart transplant (HTx) recipients, many viruses other than EBV are also infected and activated and assessment of simultaneous viral loads of other viruses is also important. In the present study, the role of simultaneous assessment of plasma and peripheral mononuclear cells for multiple viral load quantification in peripheral blood of pediatric patients after heart transplantation was elucidated. Methods In a period of 9 months (from January to October 2009) we collected 28 samples of 3 adult and 6 pediatric cardiac transplant recipients. Quantitative polymerase chain reaction for EBV, Cytomegalovirus, Parvovirus 19 (B19), BK and JC virus, and HHV6 was simultaneously performed based on the TaqMan system using DNA which isolated from peripheral mononuclear cells (PBMCs) and plasma, as described elsewhere. Phenotyping of infected lymphocytes were also done. CD8, CD19, CD45RO, CD57, etc. Results Case 1: 2-year old girl who underwent HTx at 1 year of her age, developed B cell type PTLD and died of cytokine release syndrome, showed rapid increases in EBV load in both PMBC and plasma as well as HHV 6 and B19. Case 2: 22-year female with subclinical infection for 19 years after HTx, showed sudden decrease in both in EBV load in both PMBC and plasma after conversion of everolimus to mycophenolate mofetil and both EBV loads eliminated after cytotoxic T lymphocyte (CTL) formation against EBV. Three patients (clinical in 2 and subclinical in 1) showed an increase in B19 load. Although B19 load became negative in 2 patients, B19 load sustained positive for 9 months in one patients who experienced B cell type PLTD 6 years ago and had continuous B19 infection. In one 38-year old male with steroid treatment for nephrosis and one 11-year old boy with living renal transplantation 10 years after HTx showed increases in BK and JC virus loads and an rapid decrease in both viral loads after reduction of immunosuppression. Conclusion Simultaneous multiple viral load quantifications are useful to evaluate immunosuppressive status of HTx recipients as well as monitoring of viral infection itself.

EARLY DETECTION OF CORONARY ARTERY THICKENING IN PEDIATRIC HEART TRANSPLANT RECIPIENTS USING OPTICAL COHERENCE TOMOGRAPHY

Cardiac allograft vasculopathy (CAV) is the leading cause of graft failure and mortality in pediatric heart transplant recipients, characterized by diffuse and concentric coronary intimal thickening. CAV is most successfully treated at mild stages. Thus, early CAV detection is critical because it permits earlier intervention, ultimately prolonging graft and patient longevity. Coronary angiography is the standard for CAV screening and diagnosis; however, it can underestimate disease extent, severity, and prevalence in pediatric patients, and lacks the sensitivity to detect early thickening because early vascular remodeling does not necessarily restrict luminal diameter. In addition, because of cardiac denervation during transplantation, CAV disease progression often occurs silently and may not be discovered until advanced stages. Thus, higher definition imaging modalities are required to identify early vascular changes. Coronary optical coherence tomography (OCT) is a high-definition intravascular imaging technique that may aid early diagnosis. We used OCT to investigate coronary intimal thickening in pediatric transplant recipients and examined its: 1) location (i.e. vessel type and location), and 2) nature (i.e. characteristics of cross-sectional and longitudinal thickening). Coronary angiography and OCT images from pediatric cardiac transplant recipients were collected (N=152 from 73 individuals; median age: 11.5 y (8.4-15.3); 54.1% male). OCT images were collected from the left anterior descending, left circumflex, and right coronary arteries, and classified by location (i.e. proximal, medial, and distal) using coronary angiography. OCT identified significant intimal thickening (intimal thickness >0.25 mm) in 31 pullbacks, 88% of which were angiographically silent. 88% of longitudinal thickening was segmental rather than global. 50% of cross-sectional thickening was eccentric rather than concentric (Figure 1). Thickness severity did not differ between coronary artery type, but intimal thickness was increased proximally (P=0.004). Increased age at transplant was associated with increased intimal thickness (P=0.036), and left circumflex artery thickening (P=0.004). Our study supports the efficacy and feasibility of OCT in detecting otherwise angiographically-silent intimal thickening in pediatric heart transplant patients. Early CAV detection optimizes patient outcomes. Our study also highlights the restricted description of CAV thickening as being strictly global and concentric. We postulate that the eccentric and segmental thickening detectable by OCT may represent pathophysiological processes earlier in the natural history of CAV, though further study is needed to test this hypothesis. In conclusion, OCT offers a safe, high-definition means of detecting coronary vascular changes in pediatric heart transplant recipients that may otherwise be angiographically silent.

Invited Commentary

Models of posttransplant mortality are common. They are used frequently: for prognostic information for providers and families, benchmarking of individual center results, and public reporting of those results. Each model or score has strengths and weaknesses that are predominantly determined by the data source and the methodology. The score presented in this issue of The Annals of Thoracic Surgery by O’Connor and colleagues [1O'Connor M.J. Glatz A.C. Rossano J.W. et al.Cumulative effect of preoperative risk factors on mortality after pediatric heart transplantation.Ann Thorac Surg. 2018; 106: 561-567Abstract Full Text Full Text PDF Scopus (6) Google Scholar] is paradigmatic of both the potential and the limitations of a single-center retrospective study. By identifying a series of risk factors unavailable to larger datasets, it demonstrates how the use of large dataset models of posttransplant mortality has the potential to dissuade centers from transplanting high-risk pediatric patients. Most prior models and scores predicting posttransplant mortality in children have been developed using large datasets, commonly either the Pediatric Heart Transplant Study or the Organ Procurement and Transplantation Network/United Network for Organ Sharing data [2Almond C.S. Gauvreau K. Canter C.E. Rajagopal S.K. Piercey G.E. Singh T.P. A risk-prediction model for in-hospital mortality after heart transplantation in US children.Am J Transplant. 2012; 12: 1240-1248Crossref PubMed Scopus (66) Google Scholar, 3Schumacher K.R. Almond C. Singh T.P. et al.Predicting graft loss by 1 year in pediatric heart transplantation candidates: an analysis of the Pediatric Heart Transplant Study database.Circulation. 2015; 131: 890-898Crossref PubMed Scopus (49) Google Scholar, 4Davies R.R. Russo M.J. Mital S. et al.Predicting survival among high-risk pediatric cardiac transplant recipients: an analysis of the United Network for Organ Sharing database.J Thorac Cardiovasc Surg. 2008; 135 (155.e1–2): 147-155Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar]. Organ Procurement and Transplantation Network/United Network for Organ Sharing data underlie the risk prediction models utilized by the Scientific Registry of Transplant Recipients to develop the publicly available program-specific reports (PSRs) evaluating individual center performance. These large-dataset models have the advantage of large sample sizes from multiple centers, but often lack relevant clinical information. Using a single-center retrospective analysis, O’Connor and colleagues [1O'Connor M.J. Glatz A.C. Rossano J.W. et al.Cumulative effect of preoperative risk factors on mortality after pediatric heart transplantation.Ann Thorac Surg. 2018; 106: 561-567Abstract Full Text Full Text PDF Scopus (6) Google Scholar] have identified several risk factors for posttransplant mortality that are not available in larger datasets, including single ventricle congenital heart disease, pulmonary vein stenosis, a history of greater than or equal to 4 prior sternotomies, and referral from another cardiac surgical center. Unfortunately, the methodology limits the practical applicability of the resultant score: the score is unvalidated, it suffers from the biases of the center (eg, there was only a single patient with renal insufficiency), and the increase in mortality occurred predominantly among patients with 4 or 5 risk factors (78% versus 7% to 14% in those with 0 to 3 risk factors). As the authors note, further study and validation of the score is required. However, the inclusion of these granular and specific clinical risk factors does point to the limitations of the current system of public reporting and program monitoring. Accurate models require accounting for all relevant risk models. The Scientific Registry of Transplant Recipients models used in generating PSRs fail to account for many factors that this study and others suggest are associated with high post-transplant mortality: pulmonary vein stenosis, specific congenital diagnoses, a high number of prior sternotomies, and other anatomic abnormalities. When PSRs and similar modeling are used for public reporting, regulatory oversight, and insurance contracting, centers become incentivized to avoid transplanting candidates whose risk factors are not accounted for in the modeling. Thus, while the specific score developed by O’Connor and colleagues [1O'Connor M.J. Glatz A.C. Rossano J.W. et al.Cumulative effect of preoperative risk factors on mortality after pediatric heart transplantation.Ann Thorac Surg. 2018; 106: 561-567Abstract Full Text Full Text PDF Scopus (6) Google Scholar] may have limited wider applicability, the identification of these granular risk factors and their inclusion in modeling is critical both to maximizing individual outcomes and to maintaining access to transplantation among high-risk patients. Cumulative Effect of Preoperative Risk Factors on Mortality After Pediatric Heart TransplantationThe Annals of Thoracic SurgeryVol. 106Issue 2PreviewRisk assessment in heart transplantation is critical for candidate selection, but current models inadequately assess individual risk of postoperative mortality. We sought to identify risk factors and develop a scoring system to predict mortality after heart transplantation in children. Full-Text PDF

OPTICAL COHERENCE TOMOGRAPHY IN CHILDREN: DEVELOPMENT OF A PROTOCOL FOR THE STANDARDIZED QUANTITATIVE ANALYSIS OF CORONARY ARTERIES

Optical coherence tomography (OCT) is a high-resolution intravascular imaging technique that has shown promise for the early detection of intimal thickening of coronary arteries in pediatric heart transplant recipients. The potential utility of OCT as a diagnostic and/or prognostic tool is currently unclear due to a lack of a standardized approach to analyse OCT images in this population. We established the OCT Core Imaging Laboratory at BC Children’s Hospital to develop a standardized protocol for the quantitative analysis of OCT images. Our study population included n=30 pediatric cardiac transplant recipients who had OCT imaging of the coronary arteries performed as part of standard of care at BC Children’s Hospital (St Jude Medical, now Abbott). We deemed a ‘pullback’ analyzable if ≥10mm of the segment was of good image quality (defined as ≥75% of cross-section visible without artifact). We evenly selected 10-20 cross-sectional frames ≥1 mm apart, avoiding bifurcations. Using the device-manufacturer’s software, we applied digital planimetry to trace the lumen-intima border, the internal elastic lamina, and the external elastic lamina for each cross-sectional frame. Cross-sectional areas (CSA, mm2) were derived for the lumen, the intima and the media; maximal intimal thickness (mm) was defined as the widest point between the circular markers for the intima and media. We calculated the intima/media (I/M) CSA ratio. For each pullback, we derived summary values from cross-sectional frames for relevant variables as means, medians, 95th percentile (p95) and maximal values. We performed inter-rater and intra-rater reliability analyses by intra-class correlation coefficients and Bland-Atman Analyses. Overall, 82% of analyzable pullbacks met inclusion criteria for our protocol (≥10-20 frames, ≥1 mm apart), resulting in 67 pullbacks from 28 patients analysed. The right coronary artery was most frequently imaged (58%), and more often met inclusion criteria for quantitative analyses (85% vs. 82% overall). Mean vs. median and max vs. p95 summary statistics yielded very similar values for I/M CSA and maximal intimal thickness (all ICC>0.98; difference < 3%), suggesting our protocol provides robust summary values. We registered excellent inter-rater and intra-rater reliability for I/M CSA and maximal intimal thickness (all ICC>0.95; difference < 5%). We provide a systematically developed and rigorously tested protocol for the quantitative analysis of OCT images in children. The novel application of OCT to a pediatric population requires expert image analysis and has the potential to improve the care of pediatric transplant patients who are at risk of structural coronary changes.

Hypertension in cardiac transplant recipients

Hypertension is a common syndrome in adult and pediatric cardiac transplant recipients affecting the great majority of patients. Elevated blood pressure is a major potentially modifiable risk factor associated with cardiac graft failure, vasculopathy, arrhythmias, stroke, renal failure and premature death. This review discusses the magnitude of the problem, its distinct mechanisms, and certain issues of prevention and treatment of post-transplant hypertension.

IMPACT OF OPTICAL COHERENCE TOMOGRAPHY ON MANAGEMENT OF PEDIATRIC HEART TRANSPLANT RECIPIENTS: DATA FROM THE INTERNATIONAL PEDIATRIC OCT REGISTRY

Cardiac allograft vasculopathy (CAV) is a leading risk factor for graft failure and mortality in pediatric cardiac transplant recipients. Optical coherence tomography (OCT) is a high-resolution intravascular imaging technique that has shown promise at detecting early signs of CAV which are not yet detectable by conventional angiography. We established an International Pediatric OCT Registry to: 1) evaluate the impact of OCT on clinical care; and 2) document the safety profile of this technique across pediatric centres.

Inpatient Rehabilitation in Pediatric Cardiac Transplant Recipients

Inpatient Rehabilitation in Pediatric Cardiac Transplant Recipients

Pre-Natal Diagnosis of Complex Congenital Cardiac Disease: Is There any Neuro-Developmental Benefit at 2 Years of Age?

s S95 assess cardiac anatomy. Due to the diminutive size of the cardiac structures at this early gestation, 2 Dimensional (2D) imaging alone is often insufficient to identify cardiac anatomy and great vessel relationships. We sought to evaluate the additive benefit of Color Doppler (CD) in addition to routine 2D imaging in early FE before 14 weeks GA. METHODS: From February 2009 we prospectively recruited pregnant women for first trimester FE for a variety of indications including increased nuchal translucency as well as healthy controls. All had 2D cardiac imaging combined with CD assessment. Trans abdominal scanning was used in all cases with trans vaginal scanning used additionally in most cases prior to the 11th week GA (n1⁄492/107, 86%). RESULTS: 254 pregnancies undergoing first trimester FE were included for review. Mean GA at FE was 10+6 weeks (range 6+1 to 13+6 weeks). Significant improvement in image resolution of the fetal heart was gained with every advancing week of gestation. CD significantly improved identification of cardiac arterial outflows and systemic venous inflows from the beginning of the 8th week GA through to the end of the 12th week GA (table 1). Pulmonary venous drainage was not identified in any patient until the 11th week GA. CONCLUSION: When performing early FE, prior to 14 weeks GA, identification of cardiac arterial outflows and systemic venous inflows is greatly improved by the use of color Doppler. When very early FE is performed the use of color Doppler should be routine. WCHRI 021 OPTICAL COHERENCE TOMOGRAPHY TO ASSESS FOR CORONARY ALLOGRAFT VASCULOPATHY IN PEDIATRIC TRANSPLANT RECIPIENTS A Manouzi, MC Hosking, A Fung, A De Souza, JE Potts, KC Harris Vancouver, British Columbia BACKGROUND: Optical Coherence Tomography (OCT) is a highresolution intravascular imaging technique (resolution w 10 microns) that has been used in adults to assess for coronary allograft vasculopathy. The purpose of this study is to describe technical modifications that permit its use in children and compare the coronaryfindings in pediatric transplant recipients to those seen in adults. METHODS: Pediatric cardiac transplant patients were assessed during their routine annual catheterization between December 2012 and April 2013.Modifications weremade to the traditional OCT protocol used in adults in order to adapt this technique to the pediatric population. OCT recordings (Ilumien System, LightLabs,Massachussets)were performed selectively in the right or left coronary artery. Serial measurements of the cross sectional area (CSA) of the lumen, intima and media were made along the length of the vessel. Entire imaging data was analyzed for the presence of mural thrombus, plaque and calcification. We defined the intima-to-media (I/M) area ratio as normal ( 1) or abnormal (>1) as has been done in adult transplant recipients. RESULTS: Seven patients with a history of cardiac transplant were evaluated. The mean age of children was 10.5 years (range 5.5-17) and coronary evaluation was performed a mean of 5.1 years (range 7 months to 15.7 years) following cardiac transplantation. OCT imaging demonstrated intimal thickening in 6/7 (86%) of patients, while conventional angiography was normal in all patients. The median I/M CSA ratio for all patients was 1.25 (0.94-1.79). The intima to lumen CSA ratio was 0.2 in all 7 patients. Intimal thickening was more pronounced in the proximal aspect of the coronaries (figure 1). In contrast to the findings in adults, no other vessel wall abnormalities were identified in this series of children. CONCLUSION: In pediatric cardiac transplant recipients, there are early coronary artery changes seen in the vessel wall with OCT, despite normal selective coronary angiograms. Intimal thickening is present in a significant proportion of children and is most apparent in the proximal coronaries. This is the first description of high-resolution, invivo imaging, of coronary changes in children following cardiac transplantation. 022 CORONARY ARTERY ABNORMALITIES IDENTIFIED WITH OPTICAL COHERENCE TOMOGRAPHY IN CHILDREN WITH KAWASAKI DISEASE A Manouzi, MC Hosking, A Fung, A De Souza, JE Potts, KC Harris Vancouver, British Columbia BACKGROUND: Optical Coherence Tomography (OCT) is an intravascular imaging technique allowing high-resolution

Use of a highly sensitive assay for cardiac troponin T and N-terminal pro-brain natriuretic peptide to diagnose acute rejection in pediatric cardiac transplant recipients

Biomarkers have been proposed to augment or replace endomyocardial biopsy (EMB) to diagnose acute transplant rejection (AR). A new, highly sensitive assay for troponin T detects levels of cardiac troponin T (cTnT) 10- to 100-fold lower than standard assays but has not been investigated in transplant patients. N-terminal pro-brain natriuretic peptide (NT-proBNP) has not been evaluated in pediatric transplant patients. The purpose of this pilot study was to evaluate the association of cTnT and NT-proBNP with AR in pediatric cardiac transplant patients. Plasma was obtained at the time of EMB from pediatric patients ≥ 1 year old. N-terminal pro-brain natriuretic peptide was measured in fresh plasma at the time of biopsy, and cTnT was measured from frozen, stored samples using the highly sensitive assay for troponin T. Biomarker data were correlated with EMB results. Cellular AR was defined as an International Society for Heart and Lung Transplantation biopsy score of grade ≥ 2R. Fifty-three blood samples were obtained from 42 patients (mean age 11 years). Seven episodes of AR occurred in 5 patients. Biopsies with vs without AR were associated with higher cTnT (median [interquartile range {IQR}] 66 [45-139] vs 7 [2-13] pg/mL, P = .001) and NT-proBNP (median [IQR] 11,169 [280-23,317] vs 334 [160-650] pg/mL, P < .01). After successful treatment of AR in 5 patients, cTnT fell markedly (median [IQR] 53.5 [44.8-66.5] to 10.7 [1.5-16.4], P = .05). In this pilot study, we found marked elevation of cTnT and NT-proBNP among children with AR. Moreover, reduction in cTnT levels after treatment paralleled improvement in EMB results. If these findings are confirmed in larger prospective studies, monitoring with these biomarkers may obviate surveillance EMB.

596 The Change in B-Type Natriuretic Peptide Levels over Time Predicts Significant Rejection in Pediatric Cardiac Transplant Recipients

The degree of elevation of B-type natriuretic peptide (BNP) correlates with cardiac filling pressures, the extent of left ventricular dysfunction, and worse outcomes in patients with heart failure. However, in cardiac transplant recipients, BNP levels correlate only modestly with rejection. We hypothesize that a within-individual change in BNP over time would be more helpful than absolute BNP in detecting rejection of ISHLT grade 2R or higher in pediatric cardiac transplant (tx) recipients.

Utility of exercise stress echocardiography in pediatric cardiac transplant recipients: A single-center experience

Annual coronary angiography (ANG) to assess for significant epicardial coronary artery disease (CAD) is an integral part of follow-up care for pediatric cardiac transplant recipients at Children's Hospital Boston. Exercise stress echocardiography (ESE) is an important, non-invasive tool for the detection of ischemia in adults but has been rarely used in children. Therefore, the aim of this study was to assess the feasibility and utility of ESE in excluding ANG-detected epicardial CAD at our center, where ESE has been implemented since 2007. We conducted a retrospective review of all pediatric cardiac transplant recipients at our institution who had undergone ESE and ANG between January 2007 and December 2010, and with testing performed < 12 months apart. ESE results were compared against ANG. The study cohort comprised 47 cardiac transplant recipients. One patient's ESE images were inadequate for interpretation. Of the remaining 46 patients, ESE had a sensitivity of 88.9% (95% confidence limits [CL], 51.8%, 99.7%), a specificity of 91.9% (95% CL, 71.8%, 98.3%), and a negative predictive value of 97% (95% CL, 85.1%, 99.1%) for the ANG-detected CAD. This large, single-center study showed ESE was feasible and had a high specificity and excellent negative predictive value in excluding epicardial CAD in pediatric cardiac transplant recipients. Future prospective, large-scale studies are needed to confirm these findings and help identify a subset of children for whom a negative ESE could decrease the frequency of routine ANG.

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

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. Retrospective cohort review. Tertiary pediatric transplant center in the United Kingdom. Ninety-three pediatric orthotopic heart transplants between 2002 and 2006. Total donor ischemic time was investigated for association with early post-orthotopic heart transplant hemodynamics and intensive care unit morbidities. 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. 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.

Flow-Independent Exhaled Nitric Oxide Parameters in Pediatric Lung and Cardiac Transplant Recipients

We read with interest the recent letter by Hofer et al. (1) in which airway nitric oxide (NO) in stable lung transplant recipients was compared with healthy controls using fractional exhaled NO (FeNO) measurements at variable exhalation flow rates. FeNO was similar between transplant recipients and controls at each of four fixed exhalation flows used. The authors concluded that further studies were warranted using variable flow rates, as this information could be used to differentiate between alveolar and bronchial NO production. We here provide preliminary data from a study in pediatric lung and cardiac transplant recipients using variable flow FeNO measurements. Lung and cardiac transplant recipients, without clinical or laboratory evidence of acute graft rejection, were recruited during routine hospital visits. Transplant patients were compared with healthy controls who had no history of atopy, respiratory or cardiac disease, and normal pulmonary function testing. Controls were recruited from siblings of patients and community volunteers. Respiratory infection within 3 weeks preceding the FeNO measurements was an exclusion criterion in all groups. The study was approved by the institutional review board. After obtaining written informed consent, subjects completed spirometry (2). FeNO measurements were then completed following previously published guidelines (3). FeNO was measured at expiratory flow rates of 50, 100, and 150 mL/sec using a chemiluminescence NO-analyzer (CLD 88 sp, Eco Physics, Dürnten, Switzerland). The mean of three measurements within 15% variation at each flow were used for further analysis. The flow-independent parameters, bronchial NO flux (JNO), and alveolar NO concentration (Calv) were then determined for each patient using the two-compartment model as described by Tsoukias and George (4). Comparisons were made between pairs of groups using the Mann-Whitney U test and between multiple groups using analysis of variance. Fourteen transplant recipients (7 double lung and 7 cardiac) and 21 controls were included. Mean (±SD) age at time of study was similar between transplant recipients and controls (13.9±2.0 years vs. 12.4±2.9 years). The time from transplant was longer in cardiac compared with lung transplant recipients (46.0±32.6 months vs. 11.2±89 months). Forced expiratory volume in 1 sec in percent of predicted normal values (5) were similar between controls and cardiac transplant recipients (97.2%±12.8% vs. 89.4%± 8.6%) but was significantly lower in lung transplant recipients (67.4%±22.0%, P<0.004). Similarly, forced vital capacity was comparable between controls and cardiac transplant recipients (94.6%± 12.2% vs. 85.9%±8.0%) but significantly lower in lung transplant recipients (71.1%±13.3%, P<0.003). In healthy controls, FeNO measurements were 10.8±4.0 ppb, 6.5±2.2 ppb, and 4.8±1.4 ppb at constant flows of 50, 100, and 150 mL/sec, respectively. These were not significantly different from the transplant population (12.7±4.5 ppb, 8.3±3.0 ppb, and 6.7±2.0 ppb). Subgroup analysis of the lung and cardiac groups did not demonstrate differences in FeNO (lung: 13.3±5.8 ppb, 7.9±3.5 ppb, and 6.4±1.7 ppb; cardiac: 12.1±3.1 ppb, 8.8±2.7 ppb, and 7.0±2.3 ppb). When flow-independent parameters were compared, JNO and Calv were similar between all transplant patients and controls. When lung and cardiac transplant recipients were compared separately with controls, no differences were found in JNO. However, Calv was significantly elevated in cardiac transplant recipients when compared with controls (5.5±4.0 ppb vs. 1.7±0.6 ppb, P<0.027). No such increase was seen in the lung transplant group (2.5±1.0 ppb vs. 1.7±0.6 ppb) (Figure 1).FIGURE 1.: The alveolar concentration (Calv) of nitric oxide in healthy controls, lung transplant and cardiac transplant recipients. Calv is shown for each control, lung transplant recipient, and cardiac transplant recipient. The mean Calv of each group is depicted as a line.Our preliminary data support the previously published results showing normal FeNO in lung transplant recipients (1) or cardiac transplant recipients (6) at fixed exhalation flows. However, in this pediatric population, we show a significant increase in the flow-independent NO parameter Calv in cardiac transplant recipients. The underlying cause of the increase in peripheral airways NO production in pediatric cardiac transplant recipients remains unclear, and further studies in this area are required. Our data do, however, reinforce the fact that differences in NO production in the peripheral airways may not be detected by measurements of FeNO at constant flows. The calculation of flow-independent parameters using variable exhalation flows may be needed to detect differences between groups. These parameters may become a useful tool to help diagnose clinical conditions such as bronchiolitis obliterans syndrome, infection or acute cellular rejection in lung transplant recipients noninvasively, as previous studies had suggested that these conditions may result in altered airway NO production (7–9). Larger studies will be needed to further characterize flow- independent NO parameters in solid organ transplant populations. Glenda N. Bendiak Fiona Kritzinger Anne I. Dipchand Vicky L. Ng Melinda Solomon Hartmut Grasemann Transplant Centre, Department of Pediatrics Hospital for Sick Children ON, Canada, Toronto ON, Canada University of Toronto Toronto ON, Canada

Donor‐specific HLA antibodies in paediatric cardiac transplant recipients are associated with poor graft survival

There is increasing evidence that DSA are associated with poor graft survival, although there are little data in children. We aimed to describe the incidence of DSA in this group and to determine correlation with graft survival. HLA antibodies were analysed in 59 paediatric cardiac transplant recipients. Mean age 10.4 (0.7-18.5) yr, mean time post-transplant 5.1 (0.3-17.3) yr. Antibody detection/identification was performed on the Luminex platform with subsequent identification using Lifescreen Identification kits/One-Lambda Single antigen kits. Forty patients (69%) had no HLA antibodies. DSA were found in four (7%). One had transient Class I antibodies and normal cardiac function. The other three had persistent Class II antibodies (two subsequently required re-transplantation, the third had cardiac failure due to CAV). Non-DSA were found in 15 (25%), all with normal graft function and without rejection. There was no difference in function or CAV prevalence between those with non-DSA and those without antibodies. HLA DSA is uncommon in paediatric cardiac allograft recipients but, if persistent, suggests poorer prognosis. In our series, antibodies to HLA class II on donor tissue were associated with increased graft loss. Routine screening and regular testing are recommended.

Viral Endomyocardial Infection Is an Independent Predictor and Potentially Treatable Risk Factor for Graft Loss and Coronary Vasculopathy in Pediatric Cardiac Transplant Recipients

This study sought to evaluate the outcome and prevalence of viral endomyocardial infection after cardiac transplantation. Viral myocardial infection causes heart failure, but its role after cardiac transplantation is unclear. We hypothesized that viral infection of the cardiac allograft reduces graft survival. Between June 1999 and November 2004, 94 pediatric cardiac transplant patients were screened for the presence of viral genome in serial endomyocardial biopsies (EMBs) using polymerase chain reaction (PCR) assays. Graft loss, advanced transplant coronary artery disease (TCAD), and acute rejection (AR) were compared in the PCR-positive (n = 37) and PCR-negative (n = 57) groups, using time-dependent Kaplan-Meier and Cox regression analyses. From November 2002 to November 2004, intravenous immunoglobulin therapy (IVIG) was administered to patients with PCR-positive EMBs. The outcomes of the IVIG-treated, PCR-positive patients (n = 20) were compared with IVIG-untreated, PCR-positive patients (n = 17). Viral genomes were detected in EMBs from 37 (39%) patients; parvovirus B19, adenovirus, and Epstein-Barr virus (EBV) were the most common. The PCR-positive group (n = 37, 25% graft loss at 2.4 years) had decreased graft survival (p < 0.001) compared with the PCR-negative group (n = 57, 25% graft loss at 8.7 years) and developed advanced TCAD prematurely (p = 0.001). The number of AR episodes was similar in both groups. On multivariate analysis, presence of viral genome was an independent risk factor for graft loss (relative risk: 4.2, p = 0.015). The time to advanced TCAD after becoming PCR-positive was longer in the IVIG-treated patients (p = 0.03) with a trend toward improved graft survival (p = 0.06). Viral endomyocardial infection is an independent predictor of graft loss in pediatric cardiac transplant recipients. This effect appears to be mediated through premature development of advanced TCAD. IVIG therapy in this subgroup may improve survival and merits further investigation.

521: Evaluation of Safety and Efficacy of Exercise Stress Echocardiography To Screen for Coronary Allograft Vasculopathy in Pediatric Heart Transplant Recipients

Coronary allograft vasculopathy (CAV) is the leading cause of graft loss for children who survive the first year after heart transplant. Exercise stress echocardiography (ESE) has emerged as a non-invasive alternative to screen for CAV. The purpose of this study was to review preliminary safety and efficacy of ESE for detecting CAV in pediatric cardiac transplant (tx) recipients.