The impact of flow PRA on outcome in pediatric heart recipients in modern era: An analysis of the Pediatric Heart Transplant Study database.

Data from patients in the Pediatric Heart Transplant Study (PHTS) registry transplanted between 2010 and 2014 were analyzed to determine the association between HLA antibody (PRA) determined by SPA using Luminex or flow cytometry with a positive retrospective cross-match and the post-transplant outcomes of acute rejection and graft survival. A total of 1459 of 1596 (91%) recipients had a PRA reported pretransplant; 26% had a PRA > 20%. Patients with a PRA > 20% were more likely to have CHD, prior cardiac surgery, ECMO support at listing, and waited longer for transplantation than patients with a PRA <20%. Patients with higher PRA% determined by SPA were predictive of a positive retrospective cross-match determined by flow cytometric method (P < .001). A PRA > 50% determined by SPA was independently associated with worse overall graft survival after first month of transplant in both unadjusted and adjusted for all other risk factors. In this large multicenter series of pediatric heart transplant recipients, an elevated PRA determined by SPA remains a significant risk factor in the modern era.

The Influence of Race and Common Genetic Variations on Outcomes After Pediatric Heart Transplantation.

Significant racial disparity remains in the incidence of unfavorable outcomes following heart transplantation. We sought to determine which pediatric posttransplantation outcomes differ by race and whether these can be explained by recipient demographic, clinical, and genetic attributes. Data were collected for 80 black and 450 nonblack pediatric recipients transplanted at 1 of 6 centers between 1993 and 2008. Genotyping was performed for 20 candidate genes. Average follow-up was 6.25 years. Unadjusted 5-year rates for death (p = 0.001), graft loss (p = 0.015), acute rejection with severe hemodynamic compromise (p = 0.001), late rejection (p = 0.005), and late rejection with hemodynamic compromise (p = 0.004) were significantly higher among blacks compared with nonblacks. Black recipients were more likely to be older at the time of transplantation (p < 0.001), suffer from cardiomyopathy (p = 0.004), and have public insurance (p < 0.001), and were less likely to undergo induction therapy (p = 0.0039). In multivariate regression models adjusting for age, sex, cardiac diagnosis, insurance status, and genetic variations, black race remained a significant risk factor for all the above outcomes. These clinical and genetic variables explained only 8-19% of the excess risk observed for black recipients. We have confirmed racial differences in survival, graft loss, and several rejection outcomes following heart transplantation in children, which could not be fully explained by differences in recipient attributes.

Association of race and socioeconomic position with outcomes in pediatric heart transplant recipients.

We assessed the association of socioeconomic (SE) position with graft loss in a multicenter cohort of pediatric heart transplant (HT) recipients. We extracted six SE variables from the US Census 2000 database for the neighborhood of residence of 490 children who underwent their primary HT at participating transplant centers. A composite SE score was derived for each child and four groups (quartiles) compared for graft loss (death or retransplant). Graft loss occurred in 152 children (122 deaths, 30 retransplant). In adjusted analysis, graft loss during the first posttransplant year had a borderline association with the highest SE quartile (HR 1.94, p = 0.05) but not with race. Among 1-year survivors, both black race (HR 1.81, p = 0.02) and the lowest SE quartile (HR 1.77, p = 0.01) predicted subsequent graft loss in adjusted analysis. Among subgroups, the lowest SE quartile was associated with graft loss in white but not in black children. Thus, we found a complex relationship between SE position and graft loss in pediatric HT recipients. The finding of increased risk in the highest SE quartile children during the first year requires further confirmation. Black children and low SE position white children are at increased risk of graft loss after the first year.

Outcome of listing for cardiac transplantation for failed Fontan: a multi-institutional study.

BACKGROUND: The Fontan procedure is a successful palliation for children with single-ventricle physiology; however, many will eventually require heart transplantation. The purpose of this study was to determine risk factors for death awaiting transplantation and to examine results after transplantation in Fontan patients. METHODS AND RESULTS: A retrospective, multi-institutional review was performed of 97 Fontan patients <18 years of age listed at 17 Pediatric Heart Transplant Study centers from 1993 to 2001. Mean age at listing was 9.7 years (0.5 to 17.9 years); 25% were <4 years old; 53% were United Network for Organ Sharing status 1; 18% required ventilator support. Pretransplantation survival was 78% at 6 months and 74% at 12 months and was similar to 243 children with other congenital heart disease (CHD) and 747 children without congenital heart disease (No-CHD), who were also awaiting transplantation. Patients who were younger, status 1, had shorter interval since Fontan, or were on a ventilator were more likely to die while waiting. At 6 months, the probability of receiving a transplant was similar for status 1 and 2 (65% versus 68%); however, the probability of death was higher for status 1 (22% versus 5%). Seventy patients underwent transplantation. Survival was 76% at 1 year, 70% at 3 years, and 68% at 5 years, slightly less than CHD and No-CHD patients. Causes of death included infection (30%), graft failure (17%), rejection (13%), sudden death (13%), and graft coronary artery disease (9%). Protein-losing enteropathy (present in 34 patients) resolved in all who survived >30 days after transplantation. CONCLUSIONS: Heart transplantation is an effective therapy for pediatric patients with a failed Fontan. Although early posttransplantation survival is slightly lower than other patients with CHD, long-term results are encouraging, and protein-losing enteropathy can be expected to resolve.

Rejection with hemodynamic compromise: objective evidence for efficacy of photopheresis.

BACKGROUND: Photopheresis therapy (photo) has been advocated as a therapy to improve outcome after recalcitrant or severe rejection, but objective evidence of a beneficial effect has been elusive. This study examined the hypothesis that photo provides protection against rejection, rejection with hemodynamic compromise (HC), and death from rejection after cardiac transplantation. METHODS: Between 1990 and 2003, 36 adult patients (from 343 adult transplant recipients) received at least 3 months of photo (2-day treatment every 3 to 6 weeks for a target of 18 months) after HC rejection (n = 12), recurrent/recalcitrant rejection (n = 20), or as prophylaxis in the presence of anti-donor antibodies (n = 4). Survival and risk factors were examined by analysis using multivariate hazard function modulated renewal function. RESULTS: Patients selected for photo were at greater risk for rejection (p < 0.0001) and HC rejection (p < 0.0001) than non-photo patients. After 3 months of photo therapy, rejection risk was decreased (p = 0.04). More importantly, the hazard for subsequent HC rejection or rejection death was significantly reduced toward the risk-adjusted level of lower-risk non-photo patients (p = 0.006). CONCLUSIONS: This study provides objective evidence that photo reduces the risk of subsequent HC rejection and/or death from rejection when initiated for patients with high rejection risk. Photopheresis is recommended as an important therapeutic modality after rejection with hemodynamic compromise, although further studies are needed to define the precise mechanism of the effect and the potential for benefit in other patient sub-sets.

Should status II patients be removed from the pediatric heart transplant waiting list? A multi-institutional study.

BACKGROUND: The survival benefit of cardiac transplantation (CTx) among Status 2 (stable outpatient) adult recipients has been questioned, but few studies have addressed this issue in pediatric patients. This study examined the following hypothesis: "Status 2 pediatric recipients have a survival benefit with CTx." METHODS: Between 1993 and 2003, 2,375 patients were listed for CTx at 24 institutions; 614 (26%) of these patients were Status 2. By multivariate competing outcomes hazard function analysis, death after listing and post-transplant survival were analyzed. RESULTS: A single-phase hazard function described the risk of death after listing, with 20% actual mortality within 2 months after Status 1 listing. The "natural history" of Status 2-listed patients was estimated by the risk of death, whereas waiting and risk of deterioration to Status 1 at CTx (weighted by the probability of death at 3 months after Status 1 listing). At 4 months after CTx, survival with CTx exceeded the predicted "natural Hx" survival in all diagnostic categories out to 4 years of follow-up. CONCLUSIONS: Pediatric patients currently listed as Status 2 have a survival benefit with transplant out to at least 4 years. A pediatric allocation system restricted to Status 1 patients could only be justified if the vast majority of such patients could be transplanted within 1 to 2 months.

Fate of infants with hypoplastic left heart syndrome listed for cardiac transplantation: a multicenter study.

BACKGROUND: Infants with hypoplastic left heart syndrome (HLHS) commonly undergo cardiac transplantation as primary management. METHODS: We examined outcomes of primary transplantation for unpalliated HLHS. We analyzed data from the 20 institutions of the Pediatric Heart Transplant Study Group, from January 1, 1993, through December 31, 1998, using actuarial and parametric survival analysis and competing outcomes analysis. RESULTS: During the 6 years studied, 1,234 patients were listed for cardiac transplantation; 262 patients (21.2%) had unpalliated HLHS. The number (and percentage) of patients with HLHS decreased from 58 (27% of patients listed) in 1993 to 30 (14%) in 1998. Overall, 25% of infants with HLHS died while waiting; primary cause of death was cardiac failure (50%). Of the remaining patients awaiting transplantation, 23 (9%) underwent Norwood/Fontan-type surgeries as interim palliation: 52% died. Ultimately, 175 patients underwent cardiac transplantation (67%); 50% received organs by 2 months after listing. Post-transplant actuarial survival was 72% at 5 years, with 76% of deaths (35/46) occurring within 3 months; early mortality was caused primarily by graft failure within the first 30 days after transplantation (in 54%). Among 1-month survivors, survival at 1 and at 5 years was 92% and 85%, respectively. Of the 262 patients listed with unpalliated HLHS, overall survival, taking into account mortality after listing and after transplantation, was 68% at 3 months and 54% at 5 years. CONCLUSIONS: Cardiac transplantation offers good intermediate survival for infants with unpalliated HLHS.

Evolving trends in risk profiles and causes of death after heart transplantation: a ten-year multi-institutional study.

BACKGROUND: As therapeutic options evolve for advanced heart failure, the appropriate role for cardiac transplantation will require survival analyses that reflect changing trends in causes of death and patient and institutional risk profiles. Results from multi-institutional studies could be used to monitor progress in individual centers. METHODS: Between 1990 and 1999, 7290 patients undergoing cardiac transplantation in 42 institutions entered a formal outcomes study. Changing survival, causes of death, and patient risk profiles were analyzed. Multivariable risk-factor equations were applied to a single institution (300 primary heart transplants) to examine differences in risk-adjusted expected versus observed actuarial outcomes over time. RESULTS: Overall survival in the 42 institutions improved during the decade (P =.02). One- and 3-year cardiac transplant research database survival was as follows: era 1 (1990-1992), 84% and 76%, respectively; era 2 (1993-1995), 85% and 79%, respectively; and era 3 (1996-1999), 85% and 79%, respectively. Causes of death changed over time. Pretransplantation risk profiles increased over time (P =.0001), with increases in reoperations, devices, diabetes, severely ill recipients, pulmonary vascular resistance, sensitization, ischemic times, donor age, and donor inotropic support. Three-year actuarial survival in a single institution was 3% less than risk-adjusted predicted survival in era 1, 1% higher than predicted in era 2, and 7% higher than predicted in era 3. CONCLUSIONS: Survival after cardiac transplantation is gradually improving, despite increasing risk profiles. Further improvement requires periodic re-evaluation of risk profiles and causes of death to target areas of surveillance, therapy, and research. By using these methods, progress at individual institutions can be assessed in a time-related, risk-adjusted manner that also reflects changing institutional experience, expertise, or both.

Cardiac transplant outcome of patients supported on left ventricular assist device vs. intravenous inotropic therapy.

BACKGROUND: Although the left ventricular assist device (LVAD) has been increasingly used as a bridge to transplant, its effect on post-transplant outcome is uncertain. We, therefore, designed this study using the Cardiac Transplant Research Database to compare patients supported on an LVAD before transplant with those treated with intravenous inotropic medical therapy. METHODS AND RESULTS: Of the 5,880 patients transplanted between 1990 and 1997, a total of 502 received support from LVADs and 2,514 received intravenous inotropic medical therapy at the time of transplant. Kaplan-Meier analysis showed no significant difference in post-transplant survival between the LVAD and medical-therapy groups (p = 0.09). Results of a multivariate Cox regression analysis were consistent with that of the Kaplan-Meier analysis and did not identify LVAD as a significant risk factor for mortality. The percentage of patients who received LVADs as a function of total transplants increased from 2% in 1990 to 16% in 1997. Furthermore, although the number of extracorporeal LVADs remained relatively constant, the number of intracorporeal LVADs increased over time. Multivariate parametric analysis found that the risk factors for post-transplant death in the LVAD group were extracorporeal LVAD use (p = 0.0004), elevated serum creatinine (p = 0.05), older donor age (p = 0.03), increased donor ischemic time (p < 0.0001), and earlier year of transplant (p = 0.03). CONCLUSIONS: Given a limited donor supply, the intracorporeal LVAD helps the sickest patients survive to transplant and provides post-transplant outcome similar to that of patients supported on inotropic medical therapy. Therefore, patients supported on LVADs before transplant may receive the greatest marginal benefit when compared with other transplant candidates.

Death after rejection with severe hemodynamic compromise in pediatric heart transplant recipients: a multi-institutional study.

BACKGROUND: Rejection with severe hemodynamic compromise results in high mortality in adult transplant patients. This study determines the incidence, outcome and risk factors for rejection with severe hemodynamic compromise in a multi-institutional study of pediatric heart transplant recipients. METHODS: Data from 847 patients transplanted between 1/1/93 and 12/31/98 at 18 centers in the Pediatric Heart Transplant Study were analyzed. Rejection with severe hemodynamic compromise was defined as a clinical event occurring beyond 1 week postoperatively, which led to augmentation of immunosuppression and use of inotropic therapy. Actuarial freedom from such rejection and death after rejection were determined and risk factors sought. RESULTS: Among 1,033 rejection episodes in 532 patients, 113 (11%) episodes were associated with severe hemodynamic compromise in 95 patients. The highest risk for severe rejection was in the first year. Risk factors were older recipient age (p >.05) and non-white race (p >.001). Survival after an episode was poor (60%), and biopsy score did not affect outcome. Deaths were due to rejection (n = 14), other cardiac causes (n = 17), infection (n = 5), lymphoma (n = 2), pulmonary causes (n = 2), and thrombosis (n = 1). CONCLUSIONS: Rejection with severe hemodynamic compromise occurs in 11% of pediatric patients, irrespective of age, sex or biopsy score, and mortality is high. Non-white race and older recipient age are independent risk factors for rejection with severe hemodynamic compromise. Aggressive treatment and close surveillance should be crucial components of protocols aimed at reducing the high mortality.

Are preoperative obesity and cachexia risk factors for post heart transplant morbidity and mortality: a multi-institutional study of preoperative weight-height indices. Cardiac Transplant Research Database (CTRD) Group.

BACKGROUND: The relationship between pre-transplant body weight and post-transplant outcome has only recently been identified using a single, indirect measure of weight (percent ideal body weight [PIBW]). The literature is equivocal regarding which index is the better indicator of body weight. The purpose of this study was to determine (1) if pre-heart transplant body weight, measured by body mass index (BMI) and PIBW, is associated with post-heart transplant morbidity and mortality and (2) if patient gender, age, and etiology of heart disease affect this association. METHODS: The sample included 4,515 patients who received a heart transplant from January 1, 1990-December 31, 1995 at 38 institutions participating in the Cardiac Transplant Research Database (CTRD). Patients were divided into groups according to their BMI and PIBW. Data were described using frequencies, measures of central tendency, Pearson correlation coefficients, stratified actuarial analyses and log rank tests for comparisons, and a multivariable risk factor analysis in the hazard domain. RESULTS: For all patients (n = 4,515), being <80% or >140% of IBW before heart transplant was a risk factor for increased mortality after heart transplant. The association between pre-heart transplant PIBW and post-heart transplant survival was affected by gender, age, and etiology of heart disease. In males, a higher PIBW was a significant risk factor for death early after transplant (p = .0003). Although not significant, there was a trend for a higher PIBW being a risk factor for death in females throughout the post transplant period (p = .07). No differences in cause of death were found for PIBW and BMI. In male and female recipients <55 years, being overweight pre-heart transplant was a risk factor for infection. In patients with pre-transplant ischemic heart disease, the greatest risk for infection was found in patients who were >140% of IBW. Pre-heart transplant BMI and PIBW were not associated with acute rejection or cardiac allograft arteriopathy after transplant. CONCLUSIONS: In conclusion, being cachectic or obese preoperatively is associated with decreased survival in all patients after heart transplantation. Being obese preoperatively is associated with increased infection after heart transplant in males and females <55 years and in patients with ischemic heart disease. Of the 2 indices of body weight used in this study, percent ideal body weight appears to be the better predictor of future morbidity and mortality following heart transplantation.

Induction immunotherapy in pediatric heart transplant recipients: a multicenter study.

BACKGROUND: The efficacy and safety of induction immunotherapy with antithymocyte antibody preparations (IND) in pediatric heart transplantation is controversial. Experimentally, recipient age is an important determinant of immune responses. The effects on induction immunotherapy were determined by an analysis of outcomes of 465 pediatric (age <18 years) heart recipients that either did or did not receive IND in the first week post-transplant. METHODS: The outcomes of 2 groups who received either OKT3 (n = 101) or rabbit polyclonal antithymocyte serum (N/R-ATS, n = 105) were compared with 255 recipients who did not receive antithymocyte antibodies. The study population were all heart recipients enrolled in the Pediatric Heart Transplant Study Group (PHTS) between January 1993 and December 1995 and followed up to 36 months. RESULTS: Overall mortality and death due to rejection were lowest with N/R-ATS IND (8/105 and 1/105, respectively) compared with the no-induction group (58/255 and 8/ 255, respectively) or the OKT3 group (22/101 and 7/101, respectively) with significance of p = 0.001 and 0.06 respectively. Late mortality beyond 30 days after transplant was lowest with N/R-ATS IND compared with the OKT3 and no IND (p = 0.01). Induction did not affect cumulative infections, deaths due to infection, or the frequency of malignancies. Patients excluded from N/R-ATS induction had the highest mortality (18/ 43), suggesting that the protocol's exclusion criteria identified a high-risk group. To minimize potential effect(s) of exclusion bias, patients transplanted at centers participating in the N/R-ATS induction trial were reanalyzed with a post hoc intent-to-treat analysis assigning patients by center (IND or no IND) irrespective of actual treatment. With this analysis overall mortality was 18% for N/R-ATS centers, 21% for OKT3 centers, and 26% for centers not using IND (p = 0.3). The mortalities of recipients <6 months old at transplant were lowest at centers using N/R-ATS and OKT3 IND compared to centers not using IND (p = 0.04). Cumulative rejection (0.8 vs 1.2 rejection/pt/year, p = 0.01) and freedom from rejection death (99% vs. 93% at year 1, p = 0.02) of the N/R-ATS centers were lower compared to OKT3 centers but were not different from centers not using IND. CONCLUSION: Following orthotopic transplantation, induction immunotherapy can exert the enduring benefit of reducing late deaths, a possible surrogate for rejection severity, in recipients less than 6 months of age, while not being associated with higher rates of infectious or malignant complications. Since polyclonal anti-T cell antibody preparations appears superior to OKT3 induction in pediatric recipients, the efficacy of ATS induction should be further evaluated in a randomized prospective study in pediatric heart recipients.

Replacement of the aortic root in patients with Marfan's syndrome.

BACKGROUND: Replacement of the aortic root with a prosthetic graft and valve in patients with Marfan's syndrome may prevent premature death from rupture of an aneurysm or aortic dissection. We reviewed the results of this surgical procedure at 10 experienced surgical centers. METHODS: A total of 675 patients with Marfan's syndrome underwent replacement of the aortic root. Survival and morbidity-free survival curves were calculated, and risk factors were determined from a multivariable regression analysis. RESULTS: The 30-day mortality rate was 1.5 percent among the 455 patients who underwent elective repair, 2.6 percent among the 117 patients who underwent urgent repair (within 7 days after a surgical consultation), and 11.7 percent among the 103 patients who underwent emergency repair (within 24 hours after a surgical consultation). Of the 675 patients, 202 (30 percent) had aortic dissection involving the ascending aorta. Forty-six percent of the 158 adult patients with aortic dissection and a documented aortic diameter had an aneurysm with a diameter of 6.5 cm or less. There were 114 late deaths (more than 30 days after surgery); dissection or rupture of the residual aorta (22 patients) and arrhythmia (21 patients) were the principal causes of late death. The risk of death was greatest within the first 60 days after surgery, then rapidly decreased to a constant level by the end of the first year. CONCLUSIONS: Elective aortic-root replacement has a low operative mortality. In contrast, emergency repair, usually for acute aortic dissection, is associated with a much higher early mortality. Because nearly half the adult patients with aortic dissection had an aortic-root diameter of 6.5 cm or less at the time of operation, it may be prudent to undertake prophylactic repair of aortic aneurysms in patients with Marfan's syndrome when the diameter of the aorta is well below that size.