Ten yr of pediatric heart transplantation: A report from the Pediatric Heart Transplant Study

Pediatr Transplantation 213: 17: 99 111 213 John Wiley & Sons A/S. Pediatric Transplantation DOI: 1.1111/petr.1238 Ten yr of pediatric heart transplantation: A report from the Pediatric Heart Transplant Study Dipchand AI, Kirk R, Mahle WT, Tresler MA, Naftel DC, Pahl E, Miyamoto SD, Blume E, Guleserian KJ, White-Williams C, Kirklin JK. Ten yr of pediatric heart transplantation: A report from the Pediatric Heart Transplant Study. Abstract: The PHTS was founded in 1991 as a not-for-profit organization dedicated to the advancement of the science and treatment of children during listing for and following heart transplantation. Now, 21 yr later, the PHTS has contributed significantly to the field, most notably in the form of outcomes analyses and risk factor assessment, in addition to amassing the most detailed dataset on pediatric heart transplant recipients worldwide. The purpose of this report is to review the last decade of pediatric patients listed for heart transplantation (January 1, 2 December 31, 29) and summarize the changes, trends, outcomes, and lessons learned. Anne I. Dipchand 1, Richard Kirk 2, William T. Mahle 3, Margaret A. Tresler 4, David C. Naftel 4, Elfriede Pahl 5, Shelley D. Miyamoto 6, Elizabeth Blume 7, Kristine J. Guleserian 8, Connie White-Williams 4 and James K. Kirklin 4 1 Hospital for Sick Children, Toronto, ON, Canada, 2 Freeman Hospital, Newcastle-Upon-Tyne, UK, 3 Children s Healthcare of Atlanta, Atlanta, GA, USA, 4 University of Alabama at Birmingham, Birmingham, AL, USA, 5 Ann & Robert Lurie Children s Hospital, Chicago, IL, USA, 6 Children s Hospital Colorado, Denver, CO, USA, 7 Boston Children s Hospital, Boston, MA, USA, 8 Children s Medical Center, Dallas, TX, USA Key words: heart transplant pediatric registry report risk factors outcomes Anne I. Dipchand, Labatt Family Heart Centre, Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada M5G 1X8 Tel.: 416 813 6674 Fax: 416 813 5857 E-mail: anne.dipchand@sickkids.ca Accepted for publication 19 November 212 Pediatric heart transplantation has become standard of care for end-stage heart disease in children. Over the last two decades, outcomes have consistently improved (1). The last decade has Abbreviations: CHD, congenital heart disease; CM, cardiomyopathy; CTRD, Cardiac Transplant Research database; DCC, data collection and analysis center; DCM, dilated cardiomyopathy; ECMO, extracorporeal membrane oxygenation; HCM, hypertrophic cardiomyopathy; HLHS, hypoplastic left heart syndrome; IFI, invasive fungal infection; IRB, institutional review board; ISHLT, International Society for Heart and Lung Transplantation; PCMR, pediatric cardiomyopathy registry; PHTS, pediatric heart transplant study; PJP, Pneumocystis jiroveci; PLE, protein-losing enteropathy; PRA, panel reactive antibody; PRP, percutaneous revascularization procedure; PTLD, post-transplant lymphoproliferative disorder; RCM, restrictive cardiomyopathy; SES, socioeconomic status; UNOS, United Network for Organ Sharing; VAD, ventricular assist devices. shown exponential growth in knowledge affecting the clinical course and outcomes of these unique patients. The PHTS was founded in 1991 as a not-forprofit organization dedicated to the advancement of the science and treatment of children during listing for and following heart transplantation. The purposes of the PHTS are to establish and maintain an international, prospective, eventdriven database for heart transplantation from time of listing to use the database to encourage and stimulate, basic and clinical research in the field of pediatric heart transplantation, and to promote new therapeutic strategies. Both the ISHLT and the UNOS maintain multicentre databases relevant to the field of transplantation. The ISHLT database was founded in 1981 and began data collection in 1982 with a starting point from the date of transplant (2 4). 99

Dipchand et al. With over 1 transplants in children predominantly in North America and Europe but with significant contribution from the rest of the world, it remains the largest and longest running database, with an annual pediatric registry report outlining centre activity, recipient and donor characteristics, immunosuppression trends, survival, and risk factor analyses in transplanted patients (1). The UNOS database was launched in 1987, starts at listing, reports outcomes, and facilitates selected outcomes analyses for survival and morbidities post-transplantation for the US population (5 7). However, the UNOS database has little post-transplant morbidity data available for analyses. Therefore, the establishment of the PHTS filled a significant void in the ability to study detailed clinical issues specific to outcomes following listing for pediatric heart transplantation both before and post-transplantation (8). Strengths of PHTS include both the detail and completeness of the data collected and its specificity as it relates to pediatric-related factors. This is of key importance especially with regard to patients with CHD, which is a binary element in the ISHLT and UNOS databases; the detail in the PHTS registry far surpasses what can be analyzed in the others and provides unique information that has informed practitioners and impacted practice change worldwide. Now, 21 yr later, the PHTS has contributed significantly to the field, most notably in the form of outcomes analyses and risk factor assessment, with over 7 presented abstracts and 48 published manuscripts, in addition to amassing the most detailed dataset on pediatric heart transplant recipients worldwide. The purpose of this report is to review the last decade of pediatric patients listed for heart transplantation (January 1, 2 December 31, 29) and summarize the changes, trends, outcomes, and lessons learned. The pediatric heart transplant study database The PHTS research database is currently owned and directed by the Pediatric Heart Transplant Study Foundation with significant support and infrastructure provided by the data coordinating centre at the University of Alabama at Birmingham (8). Data collection in this multicentre, prospective, event-driven database commenced on January 1, 1993, focusing on risk factors for outcome events following listing for transplantation including transplantation, death, rejection, infection, malignancy, allograft vasculopathy, and retransplantation. Currently, PHTS has 41 member institutions. As of December 31, 29, there were 35 institutions with 4319 listed and 31 transplanted patients in the database. All patients <18 yr of age listed for heart transplantation at participating institutions are prospectively entered into the database at the time of listing. Thereafter, information is gathered either annually or at the time of an event including transplantation, death, rejection, infection, malignancy, diagnosis and/or intervention for allograft vasculopathy, or retransplantation. In addition to basic clinical and demographic information, data specific to the pediatric patient population are collected (e.g., CHD diagnoses and surgeries) allowing for focused and important analyses relevant to the practice of pediatric transplantation. Over the time course of this review, there were a total of 13 data collection forms in regular use by the centers submitting data. Fields in the 1999 version of the data collection forms underwent revision and changes were implemented in 25. Most recently, there was another extensive review and revision process that resulted in the development of three new forms focused on mechanical support, renal function, and HLA antibodies. These forms were implemented in 21. All past and current versions of the data collection forms are available on the PHTS website (www.uab.edu/phts). The PHTS database is administered by the DCC at the University of Alabama at Birmingham. The DCC undergoes annual review by the IRB. The IRB requires that the DCC have a copy of each participating institution s current IRB approval. In keeping with evolving HIPAA regulations, the DCC and PHTS member institutions have reassessed and continue to evolve relevant institutional data use agreements and processes and procedures for informed consent on an ongoing basis. Quality assessments are routinely conducted to ensure that all eligible listed and transplanted patients have been submitted, all event forms (rejection, infection, etc.) for each patient have been submitted, incorrect data entry has been corrected, and missing data values have been investigated. Statistical analyses include actuarial and parametric survival analyses, competing outcomes analyses (9), and parametric multivariable analyses, usually in the Hazard Function domain (1). Further information, including a complete list of PHTS presentations and publications, membership list, forms, and a copy of the overall sections from this annual report can be found on the PHTS website at www.uab.edu/phts. 1

Ten yr of pediatric heart transplantation Observations and analyses A critical strength of the PHTS is the detailed information relevant to pediatrics available for study. PHTS analyses over the past decade have provided important insights and observations that have influenced many aspects of the practice of medicine for patients listed for pediatric heart transplantation. Moving into the next decade of this century, these detailed outcome analyses will form a basis for comparison in the evolving era of novel immunosuppressants and assist devices. Listed patients Since inception, 4319 patients (56% male) have been listed and registered in the database. Table 1 summarizes the overall characteristics of the group. Figure 1 illustrates the trends in number of patients listed over the last 1 yr. Figure 2A divides the group by major diagnosis (HLHS; other congenital, non-hlhs; CM and other). Age distribution at the time of listing is shown in Fig. 3A with 39% of patients being <1 yr of age. A breakdown of patient race at time of listing and at the time of transplant is illustrated in Fig. 4. Status at listing Figure 5A summarizes the patient status at the time of listing by year. As has been recognized within the United States (US), the majority of patients are transplanted at a high status. This has led to speculation as to the appropriateness of the current US allocation scheme for truly stratifying listed patients by clinical parameters 45 4 35 3 25 2 15 1 5 22 Number of participating institutions 23 24 24 26 29 2 21 22 23 24 25 26 27 28 29 Listed patients (n = 2858) Transplanted patients (n = 2113) 31 33 34 35 Fig. 1. Total number of patients listed and transplanted by year between 2 and 29. Non-HLHS congenital A Listing, n = 2858 All others HLHS CM B Transplant, n = 2113 Non-HLHS congenital All others HLHS Fig. 2. Patient diagnosis (A) at the time of listing and (B) at the time of transplant. HLHS, hypoplastic left heart syndrome; non-hlhs, other congenital heart disease; CM, cardiomyopathy. A Listing, n = 2858 B Transplant, n = 2113 CM Table 1. Characteristics of listed and transplanted patients 1993 29 Listed (n = 4319) Transplanted (n = 31) Demographics n (%) n (%) Male 242 (56) 1723 (56) White 399 (72) 2224 (72) Age (yr) (mean) 5.3 6.1 BSA (m 2 ) (mean).73.79 At listing At transplant Status UNOS Status 1 3283 (77) 2536 (83) Inotropes 2333 (54) 1698 (55) Ventilator 125 (28) 626 (2) ECMO 392 (9) 196 (6) VAD 113 (3) 292 (9) Clinical condition at listing Failure to thrive 691 (16) 58 (16) Renal insufficiency 155 (4) 11 (4) Donor information Ischemic time (h) (mean) (range) NA 3.7 (.5 1.5) Age 1+ yrs Age 5-1 yrs Age 1-5 yrs Age < 1 yr Age 1+ yrs Age 5-1 yrs Age 1-5 yrs Age < 1 yr Fig. 3. Patient age (a) at the time of listing and (b) at the time of transplant. such that the organs are given to the sickest recipients. In the early part of the decade using registry data, Kirklin et al. (11) demonstrated a survival advantage with transplantation for patients listed as a Status 2 out to at least four yr, supporting 11

Dipchand et al. A White Listing, n = 2858 Asian Black Other White Transplant, n = 2113 Asian Black Other Fig. 4. Patient race (a) at the time of listing and (b) at the time of transplant. A 45 4 35 3 25 2 15 1 5 35 3 25 2 15 1 B 5 the ongoing inclusion of Status 2 criteria within the allocation algorithm. In a more recent analysis in collaboration with the PCMR and looking at heart failure severity at the time of listing, no survival benefit was observed for patients not requiring intravenous inotropic support or mechanical support. In fact, mortality after listing in the low acuity cohort predominantly reflected mortality after transplantation. However, this same group of patients frequently progressed to a higher acuity while waitlisted with a biphasic hazard curve high early peak in the first month after listing followed by a low constant function thereafter. Early phase deterioration was significantly associated with a history of B Unspecified 2 1B 1A Unspecified 2 1B 1A Fig. 5. Patient UNOS status (a) at the time of listing and (b) at the time of transplant. surgery (RR 3.84), and lower LV mass z-score was a significant late (constant phase) risk (RR 1.74). No other factors were found to contribute to the risk of deterioration (12). At the latter end of the decade, more attention has been focused not only on waitlist mortality, but on the post-transplantation outcomes of high-risk waitlisted patients. Organ donor shortages have led to heightened awareness of how this scarce societal resource is utilized, most specifically concerns about sacrificing posttransplantation outcomes to decrease waitlist mortality. To this end, recent PHTS registry analyses, some outlined below, have focused on waitlist risk factors that may impact post-transplant outcomes (13 17). In fact, one analysis in particular was initiated with the goal of providing data for consideration in the revision of the existing UNOS pediatric heart allocation system in the most extreme waitlist situation: ECMO support (18). These data analyses were only possible through the PHTS database and were requested by UNOS to contribute to the revision of the allocation system. As discussed below, the data showed that pediatric patients requiring ECMO support prior to heart transplantation have poor outcomes and that serious consideration needs to be given to the candidacy of some of these patients, especially in light of the evolving and improving results utilizing ventricular assist device support as a bridge to transplant. Urgent prioritization of donor hearts to children waitlisted on ECMO on an unselected basis may not be associated with a net transplant benefit in overall patient survival due to ECMO s high post-transplant mortality. Donor data Given the challenges with donor organ availability, Conway et al. (19) utilized the PHTS database to analyze the largest cohort of pediatric heart donors (n = 3122) to better define their characteristics and determine the donor risk factors affecting recipient survival. Traditional factors often used to decline a donor heart offer were not found to adversely affect recipient outcomes including donor cause of death, donor high inotrope need, and/or donor CPR. Longer ischemic time (albeit impacted by both donor and recipient factors) did reduce survival (p =.3). In multivariate analysis (adjusted for recipient factors), for recipients <6 months of age, no donor-related factors were found to impact survival, while longer ischemic time and greater donor recipient age difference affected survival in recipients >1 yr of age. Use of hormonal therapy (defined as T3/T4, vasopressin, 12

Ten yr of pediatric heart transplantation and/or glucagon) in the donor had a significant positive impact on survival, especially early after transplant. These data will contribute to decision-making regarding donor management and the practice of donor organ acceptance, which should be tailored for age and diagnosis of the recipient. Outcomes after listing Figure 6 shows the competing outcomes for patients after listing including transplantation, death while waiting, or still waiting. Overall waitlist mortality for this decade was 11% at one year. By one-yr post-listing, 73% of patients were transplanted. Overall survival after listing has continued to improve with time with a difference even evident between the early (2 24) and later (24 29) part of the decade (78% vs. 83%, p =.3) (Fig. 7). Infants are well recognized to have the highest waitlist mortality. Further analyses of this age group are discussed below for both infant CHD and CM patients (13 17). Proportion of patients 1..9.8.7 73% Transplanted 75%.6.5.4.3.2 16% Alive 13%.1 11% Dead 12%. 6 12 18 24 Months after listing Fig. 6. Competing outcomes after listing for patients listed for transplant 2 29. Transplanted patients Since inception, 31 patients (56% male) have been transplanted. Patient characteristics at the time of transplant are summarized in Table 1. Figure 1 illustrates the trends in number of patients transplanted over the 1 yr. Figures 2B and 3B show diagnosis and age at the time of transplant, respectively. Outcomes after transplant Figure 8 illustrates overall survival post-transplant by era. There has been a significant improvement since the turn of the millennium, particularly in the latter half of the decade. Infants have the greatest early post-transplant mortality of any age group. However, their transplant half-life is approaching 2 yr in the current era, and infants who survive to one-yr posttransplant have the best long-term survival of any age group (2). Further analyses of the PHTS database for this age group are discussed below for both infant CHD and CM patients (13 17). Of increasing interest has been the difference between races in post-transplant outcomes. Singh et al. assessed the association between race and SES and graft loss in a subset of patients within the PHTS dataset using the US Census 2 database. Findings included an association between graft loss during the first post-transplant year and the highest SES quartile but not with race; however, black race and the lowest SES quartile (most specifically white race in subgroup analysis) were associated with graft loss in one-yr survivors post-transplant, pointing to a more complex relationship than previously reported (7). Beyond the impact of race, another PHTS collaborative study reported the impact of certain genetic polymorphisms on outcomes % Survival 1 9 25 29 (n = 1642, Deaths = 168 ) 8 7 6 2 24 (n = 1216, Deaths = 176) 5 Survival 4 Time 2 24 25 29 3 1 yr 78% 83% 2 yrs 77% 81% 2 p =.3 1 Event: Death after listing censored at transplant 1 2 Years after listing Fig. 7. Overall survival after listing by era (2 29). 1 25 29 (n = 1256, Deaths = 161) 9 8 7 6 2 24 (n=857, Deaths = 229) 5 Survival 4 Time 2 24 25 29 1 yr 87% 91% 3 3 yrs 81% 87% 2 p =.3 5 yrs 76% 83% 1 Event: Death after transplant 2 4 6 8 1 Years after transplant % Survival Fig. 8. Overall survival after transplant by era (2 29). 13

Dipchand et al. post-transplant, specifically acute rejection and rejection with hemodynamic compromise (21, 22). Although challenging to study, the impact of renal function on outcomes has come to light in several analyses, which are unique to the PHTS registry due to the regular annual collection of renal function parameters. Higher creatinine at transplant was a significant predictor of mortality for infants with operated HLHS on multivariable analysis (HR: 2.4, 95% CI: 1.4 4.1, p =.2) (14). Freedom from late renal dysfunction (>1 yr post-transplant) was found to be 71% and 57% at five and 1 yr, respectively, in an analysis by Feingold et al., and was associated with earlier era of heart transplant (HR 1.84, p <.1), black race (HR 1.42, p =.48), rejection with hemodynamic compromise in the first year post-transplant (HR 1.74, p =.38), and lowest quartile estimated glomerular filtration rate at one-yr post-transplant (analysis limited to estimated glomerular filtration rate >6; HR 1.83, p <.1) (23). Causes of death Overall causes of death within the PHTS dataset include rejection (18%), infection (12%), early graft failure (1%), sudden cardiac death (9%), myocardial infarction (8%, presumably related to allograft vasculopathy), and smaller numbers of other multisystem causes. A recent collaboration between the PHTS and the adult CTRD reported an analysis over time of 1 131 pediatric and adult patients looking at the relationship between age and gender to death from rejection or infection (24). Death due to rejection was highest in patients transplanted between the ages of 1 and 3 yr and lowest in those >6 yr of age, with risk factors for death being age, female gender, black race, and transplant date. Death due to infection was greatest for patients transplanted at >6 yr of age with risk factors including older age, date of transplant, younger age, and black race. Figure 9 is an example of a model illustrating the inverse relationship between infection and rejection deaths across the age span that was preserved despite the decreased incidence of both in the latter era. Daly et al. reported the incidence and risk factors for sudden death post-transplant in an analysis ranging from 1993 to 27. Of the 64 deaths in 2491 transplant recipients, 16% were sudden in nature and were associated with black race (HR 2.6, p <.1), UNOS status 2 at listing (HR 1.8, p =.8), older age (HR 1.4/1 yr of age, p =.3), and increased number of rejection episodes in the first post-transplant year (HR 1.6/episode, p =.3). The hazard of sudden death remained stable over time at.1 deaths/yr (25). Specialized patient populations ABO-incompatible infant heart transplantation. PHTS data analyses have been utilized to assess and/or propose changes in allocation strategies in the United States in comparison with others worldwide. ABO-incompatible infant heart transplantation is widely and uniformly practiced in both Canada and the UK; both countries containing transplant programs contributing to PHTS. In center and risk-adjusted analysis, there was equivalent one-yr survival and freedom from rejection in ABO-incompatible versus compatible infant recipients. However, many centers are still reserving incompatible transplantation for sick White female recipient Probability of death by 1 yr 1/1/1995 2 18 16 14 12 1 8 6 4 2 1/1/26 Infection death Rejection death 1 2 3 4 5 6 1 9 8 7 6 5 Infection death 4 3 2 1 Rejection death 1 2 3 4 7 5 6 7 Age at transplant Fig. 9. The solution of multivariate equations depicting the probability of death due to rejection or infection at one-yr posttransplantation with respect to age at the time of transplantation in white female recipients transplanted in January 1, 1995 or January 1, 26. The dashed lines represent the 7% confidence intervals. 14

Ten yr of pediatric heart transplantation patients. The data are being utilized to reexamine the current policy that gives priority to ABOcompatible over ABO-incompatible transplantation in the United States (26). Highly HLA-sensitized patients. Sensitization to HLA antibodies is an increasing challenge for potential pediatric heart transplant recipients. The development of newer HLA antibody testing modalities has outpaced our clinical understanding of the importance and impact of specific antibodies both Class I and Class II. Contributing to the literature is the PHTS analysis looking at allosensitization and outcomes wherein an elevated PRA >5% was associated with a higher risk of death waiting (19% by 12 months) and at one-yr post-transplant (73% vs. 9%, p <.1). This difference in outcome was mitigated by the presence of a negative prospective crossmatch. Interestingly, requiring further study was the lack of association between PRA level and time to first rejection or allograft vasculopathy (27). Mechanical support extracorporeal membrane oxygenation. Mechanical support has been used frequently to bridge patients to transplantation. ECMO remained the primary option for pediatric patients for a long time, but is slowly being supplanted by newer device technology. Center reports in the literature support a high waitlist mortality and survival to hospital discharge of <5% (5, 28, 29). These post-transplantation outcomes are suboptimal and bring into question the appropriateness of existing allocation algorithms and criteria for candidacy for listing. In an effort to add to the evidence base from which to define risk factors associated with worse outcomes and to gain an understanding of when it might be futile to perform a transplant on candidates on ECMO, an analysis was performed on all patients listed and/or transplanted from ECMO in the PHTS database (18). At the time of listing, there were 48/4365 patients requiring ECMO support with a survival after listing of 56% at one yr compared with patients not on ECMO at the time of listing (78%, p <.1). At the time of transplantation, 23/3132 patients were on ECMO support with a three-yr survival after transplant of 68% compared with 85% for those patients not requiring ECMO support at the time of transplant (p <.1). Thus, pediatric patients requiring ECMO support had poor outcomes and allocation of organs to these highrisk patients in an unselected manner may not be associated with an overall survival benefit. Data from this analysis are being utilized to effect change to the existing UNOS allocation policy, which is expected to be circulated for public comment in late 212 or early 213. Mechanical support ventricular assist devices. As with the ongoing drive to understand risk factors for poor outcomes in patients requiring mechanical support, the PHTS has played an important role in evaluating newer technologies for bridge to transplantation in the last decade. The seminal paper by Blume et al. (3) reported the first and largest cohort of pediatric patients bridged to heart transplantation with a VAD. Seventy-seven percent of patients were successfully bridged with post-transplant survival equivalent to patients not requiring VAD support. On the heels of this report have come the burgeoning attempts to develop pediatric-specific VAD technology. Both these data and the ECMO experience above will be utilized to benchmark the outcomes of the newer technologies as they develop. The VAD-related data within the PHTS database far exceed that contained currently within either ISHLT or UNOS and are an invaluable resource for this rapidly evolving field. Cardiomyopathies. Dipchand et al. reported on the overall outcome of CM patients listed for transplant (n = 132) in the PHTS database (13) in one of four papers on DCM, RCM, and HCM. These important papers described the clinical characteristics, defined risk factors for waitlist and post-transplant mortality, and compared and contrasted outcomes among the different groups. DCM is the most common indication for cardiac transplantation (31). In most, the underlying etiology was unknown (81%). The competing outcomes from listing showed that the final outcome was usually achieved by one yr with 1% waitlist mortality, 74% achieving transplantation and 16% remained alive waiting. Risk factors for mortality while waitlisted included history of ventilation, ECMO, and arrhythmias. For those who underwent transplantation, the mean waitlist time was 9.6 months during which clinical deterioration occurred (UNOS status 1 increased from 77% to 85%, and the number on VAD support increased from 7% to 13%). The 1-yr post-transplant survival was 72%. Risk factors for death posttransplant included black race, older age, ventilation at time of transplant, longer ischemic time, and earlier era of transplant. In an attempt to address the knowledge gap of the impact of pre-listing factors on outcomes 15

Dipchand et al. post-listing and post-transplant in patients with DCM, Pietra et al. (32) looked at a specific cohort of patients contained both within both the PHTS database and that of the PCMR. Death while waiting was only found to be associated with previously described factors: older age and mechanical ventilation. Post-transplant mortality was associated with black race, a small left ventricular dimension and, most intriguingly, a diagnosis of myocarditis despite a similar severity of illness at the time of transplantation and a higher rate of achieving transplantation. This was in contrast to the larger exclusively PHTS analysis, which did not identify myocarditis as a risk factor for survival post-transplant (31). Possible reasons for the disparate results include different patient cohorts in the separate analyses (the merger analysis was limited to the patient who overlapped both databases; there were a number of patients only included in one or the other that were not included in the data analysis), different definitions within the two databases for myocarditis, and differences in data collection strategies among others. Zangwill et al. (17) reported on 145 children with RCM comprising 11% of those with CM in the database. Their waitlisted outcome was generally achieved by one yr after listing with 9% dying, 81% transplanted, and 1% alive. Death was sudden in 2%. ECMO and VAD were significant risk factors for death (RR 11.7) as was age (especially infancy). Sixty-three percent 1-yr survival was achieved for those who were transplanted. The analysis of the PHTS of outcomes from listing of children with HCM is the largest to date of this uncommon reason for considering transplantation (15). Even so, only 7% (77 patients) of CM patients within the database had this diagnosis. They were a high-risk group 59% were UNOS status I, 3% received inotropes, 27% were ventilated, and 8% on ECMO. Arrhythmias (27%) were common and frequently ventricular in origin. Similar to DCM patients, their waitlisted outcome was achieved by one yr but their mortality was higher (13%) with fewer transplanted (65%). Younger age (particularly infants and syndromic patients) had a much worse prognosis. For those who achieved transplant, survival was also worse than for the DCM patients with only 47% alive at 1 yr. Congenital heart disease. Patients with CHD continue to represent a significant proportion of pediatric patients undergoing heart transplantation. This has changed minimally over the past decade. One of the strengths of the PHTS database is the detailed information available for patients with a diagnosis of CHD in contrast to just a categorization as is found in the ISHLT and the UNOS databases. This has allowed for multiple risk factor analyses in an attempt to better understand optimal timing of listing and risk factors for outcomes both following listing and following transplantation in this diverse and challenging group of patients. Efforts at identification of high-risk patients who may benefit from earlier listing for heart transplantation versus further staged single ventricle palliation may further improve outcomes for these complex patients. Both the UNOS and ISHLT databases have identified CHD with and without prior surgical intervention as associated with a worse posttransplant outcome (1, 33). With more detailed diagnostic information available from the PHTS database, more specific categorization of the at risk diagnostic groups has recently been possible, contributing to more appropriate decisionmaking in terms of organ allocation as donor hearts continue to be a scarce society resource. Two detailed analyses using the PHTS dataset are described below with the first focusing on the post-transplant outcomes of all infant transplant recipients <6 months of age stratified both by diagnosis and by prior surgery, and the second a more detailed look at all unoperated CHD infants in the database with a focus on the difference in the post-listing and the post-transplant survival outcomes. Everitt et al. (14) recently analyzed 739 infant heart transplant recipients <6 months of age of whom 82% had an underlying diagnosis of CHD (372 with HLHS and 235 with other forms of CHD) as well as 132 with underlying CM. Not surprisingly, patients with CM had the best posttransplant outcomes (89%, 84%, and 79% survival at one, five, and 1 yr, respectively) followed by infants with other CHD either with (82%, 77%, and 65%) or without (79%, 77%, and 65%) prior surgery. Although infants with unoperated HLHS had outcomes similar to other CHD patients (79%, 72%, 69%), infants with operated HLHS had the worst survival (7%, 64%, and 53%), particularly when infants failed palliation at <1 month of age. The hazard ratio for worse outcomes in the operated HLHS patients (HR 2.9) was similar to that for multiple risk factors (age <1 month, ECMO, and ventilator support) in the other infant groups (HR 2.45). Identification of risk factors for poor outcomes following the Norwood procedure is paramount and may allow for preferential listing for heart transplantation given the poor outcomes following failed surgical palliation in this group. 16

Ten yr of pediatric heart transplantation In a unique analysis only possible within the PHTS database, Guleserian et al. (16) recently evaluated outcomes following listing for heart transplantation in 694 infants <6 months of age with unoperated HLHS (388), unoperated non- HLHS CHD (161), and CM (145) in both early (1993 1999) and recent (2 26) eras. In the early era, one-yr survival after transplant was 92% for CM, 77% for HLHS, and 8% for non- HLHS CHD. One-yr survival after listing was only 64% for CM, 55% for HLHS, and 56% for non-hlhs CHD, indicating significant waitlist mortality. In the recent era, outcomes after transplantation for the non-hlhs CHD and CM groups were comparable with those in the early era with one-yr survival of 92% for CM and 76% for non-hlhs CHD, while there was slightly improved survival to 82% for the HLHS group. While there was an increased survival to transplant for the CM group (8%) and HLHS group (82%), indicating improved waitlist mortality, there was no improvement in survival to transplant (51% compared with 56%) for the non-hlhs CHD group. The hazard ratio adjusted for age at listing and sex was nearly twofold (HR 1.77) in the non-hlhs CHD group compared with the HLHS group and risk of death was approximately 2.5-fold after listing compared with the CM group in the recent era. Because the non-hlhs CHD infants listed for primary transplantation had <5% one-yr survival after listing due to their significant (3%) waitlist mortality, earlier listing, routine use of ABO-incompatible listing (with appropriate changes in organ allocation), and use of more liberal criteria for accepting donor hearts have been proposed to improve outcomes in this high-risk infant subgroup. In 1999, Bernstein reported results after heart transplantation in Fontan patients, a patient population that is increasingly developing endstage heart failure requiring consideration of transplantation. Although early post-transplant survival was lower than patients with other CHD and no CHD, longer-term results were encouraging and PLE was shown to resolve in all patients who survived >3 days (34). A more recent PHTS analysis focused on outcomes following the bidirectional cavopulmonary connection stage ( Glenn procedure ) (35). There was no difference in survival after listing or transplantation between this group and the patients transplanted following Fontan procedure with similar risk factors for mortality in both groups (mechanical ventilation, UNOS status, and age). Mechanical ventilation and transplantation <6 months post-fontan procedure were associated with significantly higher mortality in the Fontan patients. Post-transplant complications Rejection. Early rejection information derived from the PHTS database is particularly important as ISHLT can only track rejection following hospital discharge. Within the PHTS database, freedom from first rejection was 83% at one month and 64% at one yr (Fig. 1). Multiple analyses have continued to confirm the relationship between non-white/black race, cumulative episodes of rejection, and late rejection as risk factors for poor outcome, including death, retransplant, and allograft vasculopathy (7, 36). With dramatic improvement in long-term survival in the past decade for all recipient age groups, the PHTS embarked on a reanalysis of rejection to determine whether there were erarelated effects on the occurrence of allograft rejection with three sub analyses: (i) overall incidence and prevalence of rejection over time; (ii) rejection with hemodynamic compromise; and (iii) late rejection comparing early to recent era. Focusing specifically on the first year posttransplant, the incidence of rejection declined from 1993 to 25 from 6% to 4% (p <.1), as did the number of episodes of rejection per patient (1.19.66; p <.1); however, the incidence of rejection with hemodynamic compromise and death from rejection in the first year post-transplant did not change. Risk factors for rejection included positive donor-specific crossmatch and older recipient age (37). The subsequent analysis of rejection with hemodynamic compromise showed a similar survival for severe episodes between an earlier era and the most recent era (63% at one yr and 49% at five yr) despite more aggressive treat- % Freedom from rejection 1 9 Interval % Freedom 1 month 81% 8 1 yr 64% 7 3 yrs 56% 6 5 yrs 52% 5 4 3 2 1 Event: First rejection 2 4 6 8 1 Years after transplant Fig. 1. Freedom from first rejection (2 29) 17

Dipchand et al. ment strategies. Risk factors included non-white race, older age, and non-a blood type (38). Finally, an analysis looking at late rejection (>1 yr post-transplant) demonstrated an overall decrease in both first and recurrent late rejection (36). Late rejection was also significantly associated with early rejection <1-yr post-transplant. Additional risk factors were earlier era, nonwhite race, older recipient age, recipient status 2 at transplant, and male donor. Mortality and risk of moderate to severe allograft vasculopathy or re-transplantation remained similar across the earlier and more recent eras. Recipients with late rejection after early rejection had significantly increased risk of developing moderate to severe allograft vasculopathy (OR 4.4, p <.1). % Freedom from infection 1 Interval % Freedom 9 1 month 87% 8 1 yr 72% 7 3 yrs 62% 6 5 yrs 57% 5 4 3 2 1 Event: First infection 2 4 6 8 1 Years after transplant Fig. 11. Freedom from first infection (2 29) Infection. Freedom from first infection was 72% at one-yr post-transplant (Fig. 11). Looking at changes in practice patterns and impact on patient outcomes, Gajarski showed that the use of induction therapy increased from 57% in 1993 1998 to 71% in 1999 28, with no concomitant increased risk of overall infection or malignancy (39). Cytomegalovirus infection was the focus of a PHTS analysis to determine the impact of recipient CMV status and CMV mismatching on posttransplant outcomes, and to look at the influence of prophylaxis (4). Prophylaxis was found to have been used in 67% of recipients, predominantly in the setting of CMV mismatch (donor positive, recipient negative). Freedom from clinical CMV infection was 91% at five yr, with an increased risk in the setting of CMV mismatch (p <.1), but with no difference in relation to the use of prophylaxis. Neither recipient pretransplant CMV positivity nor the use of prophylaxis was found to be associated with death or development of allograft vasculopathy, pointing to the clear need for a better understanding of the best approach to the prevention of CMV disease in this patient population. Another transplant-related opportunistic infection for which widespread prophylaxis is commonplace is PJP. In an attempt to establish the current prevalence and outcomes, Zaoutis and Ng undertook an analysis of the PHTS database (41). In a broad look at post-transplant infections (n = 238 in 122 patients), 54% were bacterial, 32% viral, 7% fungal, and.5% protozoal. Of the fungal infections, only 13% (n = 18) were due to PJP resulting in a rate of PJP infection of 1% and an incidence of 2.6 infections for every 1 patient years. Risk was highest in recipients <1 yr of age at the time of transplant. Percent freedom from PJP for pediatric heart transplant recipients was 98.8% at 1 yr, and PJP was the cause of death in.5% of the entire patient population. Another look at a rare occurrence was a review of IFIs, making up 7% of the post-transplant infections (42). IFIs were most commonly due to yeast (66%), predominantly Candida and Aspergillus spp, and were associated with incremental numbers of invasive pre-transplant procedures (e.g., ECMO, prior surgery, VAD, and mechanical ventilation). Mortality was high at 49% and occurred predominantly within sixmonth post-transplant pointing to the need for consideration of prophylactic strategies in the population at risk. Malignancy. PTLD remains a barrier to longer-term survival post-heart transplantation in children. Previously, the PHTS reported a probability of survival following diagnosis of 67% at five yr (43). In a more recent analysis of 317 patients over 16 yr, freedom from PTLD was 9% at 1 yr, but when age-stratified, children aged 1 9 yr were at the highest risk compared with infants (RR 2.4) and adolescents (RR 1.7). Strikingly, one-quarter of children aged 4 7 yr who were negative for EBV but received an organ from an EBV-positive donor developed PTLD. Most importantly, and not previously shown, the hazard for PTLD continues to increase with time post-transplant (Fig. 12) (44). Allograft vasculopathy. Transplant coronary artery disease or coronary allograft vasculopathy is one of the leading causes of late morbidity and mortality in heart transplantation. Another strength of PHTS is the ability to review and analyze events with very low rates of occurrence that would preclude meaningful single centre analyses, again also not possible within the 18

Ten yr of pediatric heart transplantation Percent freedom from PTLD 1.5 Survivorship 95 9.4 Freedom from PTLD 85 Time Pct 95%CL 8 1 yr 98.5% 98% 99%.3 75 3 yrs 96 95% 97% 7 5 yrs 94 93% 95% 1 yrs 9 88% 92%.2 65 15 yrs 87 84% 9% 6.1 55 Hazard 5 2 4 6 8 1 12 14 16 18. Years after transplant Fig. 12. A Kaplan Meier estimate of freedom from PTLD and the hazard for PTLD as a function of time post-transplantation. A steady decline in freedom from PTLD was observed over time. The peak hazard for PTLD occurred at 5.6-month post-transplantation. Dotted lines depict the 95% confidence limits. ISHLT or UNOS databases. One such example is the use of PRPs for allograft vasculopathy. Despite 3156 transplant patients in the database, there are only 46 reports of PRPs in 26 patients. Despite technically successful interventions, graft loss occurred in 52% within one-year post-procedure, pointing to the temporizing nature of these interventions and the need to consider concurrent listing for retransplantation if appropriate (45). The last large-scale review of allograft vasculopathy in the PHTS database was by Pahl and colleagues in 1222 children transplanted from 1993 to 21 (46). This remains the largest cohort reported in the literature to date. As we enter the next decade and have new influences including a much larger number of recipients who have a longer survival post-transplant, changes in immunosuppressive agents, a new ISHLT grading system for allograft vasculopathy (47), differing surveillance strategies, different risk factors including transplantation in the face of a positive crossmatch, and increasing recognition of donorspecific anti-hla antibodies, the PHTS has embarked upon an large-scale analysis on allograft vasculopathy, the results of which are sure to provide further insight into this challenging post-transplant morbidity. Retransplantation. As pediatric recipients age, graft failure and the need for retransplantation has increased. Due to the still relative rarity of this practice, in 26 PHTS published the first registry-based study examining the incidence and outcomes of pediatric retransplantation (48). For the 62 subjects retransplanted between January 1993 and December 24, the most common Hazard for PTLD indication for a second transplant was allograft vasculopathy. Other indications for retransplantation included rejection-related graft failure, early graft failure, and other/unknown causes. The mean time from initial to second transplant was 3.7 2.8 yr. Although overall survival for retransplantation was lower than primary transplantation, the timing of retransplantation was an important factor. For those patients retransplanted early (<12 months after initial transplant), survival was significantly lower, while survival of those retransplanted late ( 12 months after initial transplant) was comparable with primary transplantation. Retransplantation outcome was also influenced by indication for retransplantation, with those undergoing retransplantation secondary to acute rejection and early graft failure having the worst survival. Summary Key PHTS analyses over the last decade provide evidence to contribute to evolving changes in organ allocation schema. Survival advantage for UNOS Status 2 patients was shown early in the decade. Patients requiring ECMO support have poor outcomes, and urgent prioritization on an unselected basis may not be associated with a net transplant benefit. Risk factors were identified that contribute to decision-making regarding listing dilated, restrictive, and HCM patients for transplant, in addition to providing important information for counseling families on outcomes. Infants with CHD and failed surgical palliation were shown to do particularly poorly, and this needs to be factored into management algorithms for this patient population. Survival analyses continue to show improvement, even within the latter half of the last decade. There are significant age-related differences in death from rejection or infection and in the incidence of PTLD, which have important implications for the immunosuppressive and post-transplant management across the pediatric age range. Early and late rejection has decreased over time except for rejection with hemodynamic compromise and death due to rejection in the first year, despite more aggressive treatment regimens. Allograft vasculopathy, related mortality, and need for retransplantation remain unchanged and indicate the need for a better understanding of these ongoing challenges that limit long-term survival. Moving forward Over the last 21 yr, the PHTS has made major contributions to the outcomes relevant to 19

Dipchand et al. pediatric patients listed for heart transplantation including risk factors for these outcomes. Looking forward to the next decade, key issues are likely to be (i) the evolution of newer technology for mechanical support and the inevitable impact on both the characteristics of patients waitlisted for transplant and on post-transplant outcomes; (ii) the prevalence, significance, and impact on outcomes of both pre-existing and de novo donor-specific antibodies; (iii) further long-term understanding of allograft vasculopathy; (iv) the transition from pediatric to adult care; and (v) risk factors analyses and impact on decisionmaking regarding candidacy for transplantation and post-transplantation outcomes. The existing scientific contributions from the PHTS will foster benchmarking for newer clinical practices and evolving technologies, while ongoing prospective data collection will allow for further assessment of the same. 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