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Outcomes following heart transplantation in children
Progress in Pediatric Cardiology 26 (2009) 39 – 46 www.elsevier.com/locate/ppedcard
Outcomes following heart transplantation in children W. Robert Morrow ⁎ Division of Pediatric Cardiology, Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, AR, United States
Abstract After nearly 30 years of heart transplantation in children, following the introduction of cyclosporine, it is clear that early and intermediate survival following transplantation is good. Actuarial survival at one year, 5 years, 10 years are 85%, 75%, and 64% respectively. Fifteen year actuarial survival in the ISHLT Registry is approximately 47%. Naturally, late survival reflects early experience with transplantation in children and a worst case scenario. Recent studies show that survival is improving owing almost entirely to reduced early mortality after transplant. Survival at five years in the current era, 2001–2005, is 77% compared to 72% for the era 1993–2000. Multiple factors may account for this reduced early mortality including better peri-operative management, improved immunosuppression but also better case selection and earlier referral. However, despite improving results and reduced early mortality, there is an ongoing constant phase of mortality, approximately 3% per year, resulting in decreasing survival with time. This ongoing risk of death has persisted but may be less in the current era due to improvements in immunosuppression. Important differences in survival exist between patients of different age at transplant. While early survival in infants is less than in older children, late survival and overall survival is better. For those infants surviving at least one year after transplant subsequent ten year survival is approximately 80% compared to 70% for children 1–10 years of age and 60% for children 11–17 years of age. Of note, the constant hazard for death appears to be less the younger the infant is at transplant, compared to older children. This may represent a degree of conditional tolerance in the youngest infant. Patients with congenital heart disease have good survival following transplant but less than patients with cardiomyopathy or myocarditis. However, for patients with failed Fontan palliation for single ventricle survival is comparable to other patients with congenital heart disease. Outcomes for patients requiring mechanical support are poor for patients bridged to transplant with ECMO but are equivalent to other Status 1 patients for those on left ventricular assist devices (Thoratec, HeartMate, Abiomed, etc.). Outcomes of bridge to transplant with Berlin EXCOR appear to be superior to ECMO but a multi-center study is underway. Despite discouraging late survival estimates based on historical experience, improving survival in more recent eras will probably result in improved long term survival in future years. Development of new strategies for immunosuppression, particularly those aimed at reducing graft loss from chronic rejection, may also significantly improve long term survival. In addition, tailoring therapy to those who are at high risk, including those with high risk due to elevated PRA and those with other risk factors may improve long term survival. © 2008 Published by Elsevier Ireland Ltd. Keywords: Heart transplant; Cardiac; Heart disease; Antibodies
1. Introduction Although the first heart transplant in a child was reported by Kantrowitz in 1968 [1], widespread use of transplantation for lethal heart disease in children only became practical following ⁎ Division of Cardiology, Arkansas Children's Hospital, 800 Marshall Street, Little Rock, AR 72202, United States. Tel.: +1 501 320 1479; fax: +1 501 320 3667. E-mail address: [email protected]. 1058-9813/$ - see front matter © 2008 Published by Elsevier Ireland Ltd. doi:10.1016/j.ppedcard.2008.10.005
the introduction of cyclosporine in the early 1980's. The registry of the International Society for Heart and Lung Transplantation (ISHLT) records 6979 cardiac transplant procedures in children ranging from 11 transplants in 1982 to a peak of 403 in 2005 [2]. Fortunately, with improvement of preoperative assessment, patient selection, post-operative care, and immunosuppression, survival following heart transplantation in the pediatric patient is good. Early, intermediate, and late survival has been reported from many institutions, multiinstitutional studies, and registries [2–19]. Published experience
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demonstrates varying survival by center, patient age at transplant, diagnosis at listing and era of transplant in addition to a number of other pre-transplant risk factors. In addition to mortality after transplantation, mortality for potential transplant recipients is significant prior to transplantation. However, as experience has increased survival both before and after transplantation has improved. While there are many potential outcomes to consider, including patient survival, graft survival, developmental and social outcome, and others, this discussion will be confined to patient survival. Survival of listing and survival inclusive of pre-transplant and post-transplant mortality has been reviewed elsewhere [18,19]. Here we will also limit our review to survival of children after transplantation only, with an emphasis on late outcomes. We will also focus on outcomes in specific age groups, pre-transplant diagnoses, and special circumstances. An important general feature of survival following transplantation is that there is a consistent early phase hazard for mortality followed by a constant hazard. This means that early after transplantation the risk of death is highest (an exponential function) but short lived and is followed by a risk of mortality that represents a constant annual risk of death (linear slope). The continuing constant phase of mortality produces an inexorable decline in survival with each subsequent year post-transplant. 2. Early and intermediate term survival in children A number of institutions have reported excellent early and intermediate post-transplant survival in both infants and children [3–17] following cardiac transplantation. It is impos-
sible to compare results between individual centers and multicenter reports because of differences in recipient selection, era of transplant, evolving surgical experience, and differences in immunosuppressive and surveillance regimens. In most single center reports statistical analysis of risk factors for death, if it is performed at all, is limited to univariate techniques because of small numbers. While the early outcomes following transplantation in children had been reported by the ISHLT Registry, these initial reports lacked complete data submission and meaningful risk factor analysis. For this reason, the Pediatric Heart Transplant Study Group (PHTS), which began data collection in 1993, undertook an analysis of outcomes of transplantation of early survival after transplantation in infants and children. Shaddy et al., reported this initial PHTS survival experience and risk factor analysis among 191 children older than one year of age who underwent transplantation [20]. Actuarial survival after transplant at 1 month was 93% and was 82% at one year. By multivariable analysis the major risk factor for death was the need for assist devices at the time of transplant (p = 0.02). Nonetheless, overall survival after transplantation among Status 1 and Status 2 patients was not different. Younger age in this group of patients over one year of age at transplant was a significant risk factor for death in the multi-variable analysis. Patients in the 1–5 year age range had a one year actuarial survival of 74% compared to 86% for patients over five years of age at transplant. These single center reports, the initial ISHLT registry reports, and early PHTS experience were all published in the early 1990's. Thus they represent the earliest experience with pediatric transplantation in the cyclosporine era. Subsequent
Fig. 1. Actuarial survival in the most current PHTS analysis among 1978 patients undergoing primary heart transplantation. A short early phase hazard for mortality is seen prior to 6 months post transplant with an ongoing constant hazard for death thereafter. Survival is 85% at one year, 75% at five years, and 64% at ten years.
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reports by the PHTS [18–19,21–24] have shown five year survival following transplantation of approximately 75%. In the most recent analysis of the PHTS data including 1978 patients undergoing transplantation, 38% were less than one year, 37% were between one and 12 years, and 25% were greater than 12 years of age at transplant. 69% of patients were Status 1 or Status 1A. Overall actuarial survival after transplantation for all age groups was 85% at one year and 75% at five years (Fig. 1). Neither urgency status at transplant or ischemic time affected five year survival. This is in keeping with more recent registry reports of the ISHLT database although 5 year survival in the most recent registry report ranges from approximately 68% depending, possibly due to the inclusion of patients transplanted in the decade before the PHTS. 3. Early and intermediate survival in infants Bailey et al. [3] at Loma Linda pioneered infant transplantation in the early days of the cyclosporine era. Survival after transplantation in the Loma Linda experience was initially 85% at one year and 80% at five years in 139 infants who underwent heart transplantation for a variety of diagnoses. In a group with HLHS survival after transplantation was similar with a five-year actuarial survival of 74% [7,14,16]. By far most mortality was early, even peri-operative, and was the result of early graft failure due to primary graft dysfunction, pulmonary hypertension, or technical factors. Others have also reported excellent survival in this age group as well [4,17]. Canter et al. [25] examined early survival after heart transplantation in the PHTS experience among infants less that one year at transplant. The majority of infants (66%) had hypoplastic left heart syndrome. Survival was less than in older children with 70% of infants surviving at one year compared to 82% in children older than one year. The peak hazard for death was within the first month post transplant (early phase) with 16% of patients dying in this interval. Risk factors for death included a history of previous sternotomy (p = 0.0003) and a donor cause of death other than closed head trauma. Previous history of sternotomy in this age group implies a very recent but failed attempt at repair and, therefore, represents a particularly high risk group of patients. Most deaths early after transplantation occurred as a result of graft failure or pulmonary hypertension. When combined these two causes of death accounted for 75% of deaths in the infant age group. In the most recent PHTS analysis (unpublished) survival among infants less than 6 months of age at transplant was 82% at one year and 66% at 10 years post transplant compared to older children where one year survival is 88% and 10 year survival is 55%. This observation of greater early mortality but less intermediate and late mortality is important and has been confirmed by other centers as well as analysis of the ISHLT Registry data. 4. Late survival For the purposes of this report late survival is defined as survival after 10 years following transplantation. While this may be an acceptable definition for adults undergoing transplantation, the
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reasonable expectation of greater longevity in children undergoing transplantation should provoke a sober look at survival at greater than 15 to 20 years. Data are only now becoming available for such long term survival at 15 to 20 years and are largely provided by the ISHLT registry report and single institution reports of programs with early experience with heart transplantation in children. The obvious limitation of such data is that it is from the earliest era in transplantation during a steep clinical learning phase. Late survival at Stanford was low with a reported 10 year survival of 60% [10,11]. Importantly, the Stanford program pioneered heart transplantation in children and many patients in this series underwent transplantation prior to the cyclosporin era. Sigfusson et al. [26] analyzed “conditional” survival from the experience of three institutions with long term experience. In that analysis actuarial survival of patients who had survived at least five years was 80% at ten years post transplant but 67% at 15 years emphasizing ongoing mortality, primarily due to acute rejection and graft atherosclerosis. Again, only patients who had survived at least five years were included in the analysis and, therefore, these data do not reflect overall 10 and 15 year survival. Webber reported a 10 year survival of approximately 45% in a cohort of 37 patients transplanted between 1982 and 1989 [15]. However, in this same cohort five year survival was approximately 50%, less than what has been achieved at other institutions in more recent cohorts. In the same report Webber notes a much improved contemporary four year survival of greater than 90% implying the potential for much improved long term survival of this more recent cohort. Fifteen year actuarial survival for the earliest cohort of patients in the ISHLT registry (1982–1988) is 40%. However, for this same cohort actuarial survival at 5 years was 58% whereas the actuarial survival at 5 years in a more current era (1999–2003) is 70%. Most of this improving survival benefit is seen in the six months following transplant, indeed within the first month. Risk factors for death after transplantation at one year were need for a ventilator prior to transplant and hospitalization prior to transplant, both indications of a decompensated, severely ill patient. Interestingly, neither donor ischemic time or transplant center volume were risk factors for death after transplantation, in contrast to previous analyses of the ISHLT registry data. The ISHLT registry report gives a 15 year actuarial survival of approximately 40% for all ages [2]. However, if a recipient survives at least five years after transplant subsequent conditional 15 year survival is 65% (after five years post transplant). For infants who survive at least five years conditional survival is predicted to be 80%. The PHTS experience [19,22] confirms the presence of an ongoing constant phase of mortality (Fig. 1) which could result in a fifteen year survival in the range of 45%. However, it is very likely that improvement in early survival described above will translate to better long term survival for patients transplanted in the current era. The continuing occurrence of late rejection [28], rejection deaths [29], graft atherosclerosis [29–31], and lymphoproliferative disease [32] accounts for the continued intermediate and late mortality and raise concern about the ultimate fate of children who have undergone cardiac
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transplantation. The most recent analysis of the PHTS data (unpublished) suggests improving survival in the constant phase (p = 0.02) for the era after 1997 although the actual effect this reduction in mortality is small. 5. Late survival in infants As noted above, the Loma Linda experience [19,27] and analysis of the PHTS data have demonstrated a better long-term survival in neonates with HLHS compared to older infants. From 1985 through 2004, 282 infants underwent transplantation at Loma Linda [19,28]. Patient survival among newborns (less than 30 days at transplant) was77% at 10 years and 71% at 15 years compared to 54% at 10 years and 48% at 15 years for infants (p = 0.0029). Actuarial graft survival, including graft loss in patients who underwent re-transplantation, was 71% at 10 yrs, 62% at 15 yrs for newborns and 47% at 10 yrs, 40% at 15 yrs for infants (p = 0.002). Younger age at transplant was associated with a decreased risk of graft loss. Similarly, in a recent analysis of the PHTS data (2004), one year survival in infants less than 6 months at transplant was 80% and was 70% at 9 years compared to older children where one year survival was 87% and 5 year survival was 66%. Thus patients transplanted as newborns fared better than infants and infants fared better than older children. In the analysis of the Loma Linda experience, Chinnock [28] examined the contribution of immunological factors, rejection history and graft loss due to rejection or post-transplant coronary artery disease. Long-term actuarial freedom from rejection was 23% (10 yrs and above) for infants versus 8%
(10 yrs and above) for newborns (p = 0.003). However, actuarial freedom from graft loss due to rejection or post-transplant coronary artery disease was 59% at15 yrs for infants compared to 84% at 10 yrs, 78% at 15 yrs for newborns (p = 0.009). In the most recent analysis of the ISHLT Registry data [2] there appears to be a clear survival advantage in children transplanted at less than 1 year of age compared to older children. While the early phase risk of death was greater than older children the constant hazard for death appeared to be less. This was best seen in the analysis of conditional survival. For infants less than one year of age surviving at least one year after transplant the subsequent 15 year survival was 67% compared to 55% for children 1–10 years of age. Likewise, for the same groups surviving at least 5 years the subsequent 10 year survival was 80% for infants transplanted at less than a year of age and 67% for children 1–10 years of age at transplant. The reasons for better long-term survival in infants are multifactorial. However, earlier age at transplant is associated with improved patient and graft survival and is likely related to immunologic factors. This may have implications for use of ABO-incompatible donors. A strategy which uses a prolonged waiting time before proceeding to accepting an ABO incompatible donor could potentially disadvantage the neonatal recipient. West et al. [33,34] reported their experience with ABO incompatible heart transplant in neonates and infants. Overall survival was 80 percent. Interestingly, these infants did not experience hyperacute rejection and the only deaths which occurred were not related to ABO incompatibility. Most patients did not develop antibody to donor blood group although two did without apparent graft damage.
Fig. 2. Actuarial survival in pediatric heart transplant recipients (n = 1978) stratified by era of transplantation. Survival is significantly better after 1995 compared to before. Improvement in survival is seen early after transplantation and in the era beginning in 1997 for the constant hazard for death (p = 0.02).
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The apparent long term survival advantage strongly argues for a strategy of primary transplantation for infants who have poor medical or surgical options. Of great interest is the apparent divergence in the constant phase hazard for death in neonates and infants from older children. It is important to remember, that the patients with the longest survival (or late mortality) were transplanted in an era which preceded widespread use of newer immunosuppressive regimens including tacrolimus, mycophenolate, sirolimus, and humanized or chimeric IL-2 receptor antibodies and were based primarily on triple immunosuppression with cyclosporin, azathioprine, and corticosteroids. Recent evidence suggests that combination therapy with these newer agents may significantly improve early and intermediate survival [35]. It is unclear at this point whether these interventions will alter the slope, or rate of death after transplant in the constant phase. 6. Improving survival — an era effect? Several recent publications from the PHTS experience have reported an improving overall survival [18–19,22]. Essentially, survival in patients at PHTS centers was significantly better after 1995 compared to prior to that time. In the most recent analysis (Fig. 2), 5 year survival was 72% for the era 1993– 2000 compared to 77% for the era 2001–2005 (p = 0.01). At this point, implementation of the new UNOS urgency status designation in January of 2001 does not appear to have had any impact on post-transplant survival [36,37]. Similar outcomes have been reported in the most recent ISHLT Registry report [2]. Survival was significantly better after 1990 than before and better after 1995 than in the era from 1990–1994. A close examination of the actuarial survival curves in the ISHLT and PHTS studies demonstrates that the greatest improvement in survival occurs within months following transplant while a constant hazard for death following transplant begins within 6 months of transplant. In fact, most of the improvement in survival can be accounted for by decreased early mortality. Previous analyses of the ISHLT data and the PHTS data have indicated that the constant hazard for death has remained unchanged despite improvements in early survival. However, the most recent analysis of the PHTS data (unpublished) has shown improving survival in the constant phase (Fig. 2). There are many potential reasons for improved survival in the early phase after transplantation. Certainly pre and post operative management has improved including use of nitric oxide and ECMO for rescuing patients with pulmonary hypertension and right ventricular failure. But other factors may play a significant role as well including earlier referral for transplantation, better case selection, fewer low volume centers, and less highly toxic induction regimens. While not playing a role in reduced early mortality to date, elucidation of specific genetic risk factors in the form of polymorphisms which are associated with increased risk of rejection and/or altered metabolism of immunosuppressive agents may allow better tailoring of maintenance immunosuppression to specific patient risk [38,39].
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7. Survival after transplantation for congenital heart disease Patients with congenital heart disease account for roughly half of all pediatric patients undergoing heart transplantation [2] depending on the age of the patient. Outcomes for infants with hypoplastic left heart syndrome are summarized above. Survival in the early experience with patients with other congenital heart defects initially appeared to be lower than survival in patients with acquired heart disease [8,9]. More recent experience [2,22–24] suggests that there may be in fact a difference in survival among children who undergo heart transplantation for a primary indication of congenital heart disease when compared to those without congenital heart disease. A pre-transplant diagnosis of congenital heart disease was not an independent risk factor for death in the initial PHTS experience. However, if one specifically excludes infants with hypoplastic left heart syndrome, subsequent analysis demonstrates that early survival in patients with cardiomyopathy or myocarditis is superior to survival in patients with congenital heart disease [23]. A special group of patients are those with a failed Fontan repair for single ventricle. These patients undergo transplantation for a variety of indications, the most common being protein losing enteropathy or “right heart failure”. Transplantation in this group can be performed with good survival [40–43] and with anticipated improvement in protein losing enteropathy. In the series reported by Bernstein [40] from the PHTS, actuarial survival after transplant was 77% at one year and 67% at five years (Fig. 3). This survival was no different from patients with congenital heart disease older than one year of age at transplant (excludes primary transplant in patients with HLHS) but was lower than those with cardiomyopathy. Importantly, time since repair in this and other lesions seems to be important in predicting survival. Transplantation performed early after repair in an attempt to salvage patients is more likely to result in death than transplantation many years after repair. In contrast to all
Fig. 3. Actuarial survival after transplantation in pediatric patients undergoing transplantation for failed Fontan procedure (40). There is no significant difference in survival after transplant in patients with prior Fontan palliation compared to patients with other repaired congenital heart defects. (used with permission, Circulation).
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other diagnostic groups, the most common cause of death in patients transplanted for failed Fontan is infection. Patients with protein losing enteropathy who have severe nutritional deficiency and wasting are at greater risk of death from infection after transplantation due to immunodeficiency and poor healing associated with longstanding malnutrition. Clearly, appropriate patient selection is key to successful surgical repair and some patients with single ventricle physiology are better served by primary transplantation rather than attempts at surgical palliation with Fontan repair or revision of previous Fontan [42,43]. For survivors, resolution of protein losing enteropathy is the rule but many have persistent hypoalbuminemia and protein loss for months following transplantation [38]. 8. Impact of mechanical device support on survival In the Pittsburgh experience [15] an important risk factor for death in Status 1 patients was the requirement for a mechanical assist device prior to transplantation. Until recently, in the pediatric age group this usually meant the use of extracorporeal membrane oxygenation (ECMO) although a variety of left ventricular assist devices are used including centrifugal pumps functioning as left ventricular assist devices as well as Thoratec and Heartmate left ventricular assist devices in adolescents. The most recent ISHLT registry analysis demonstrates that ECMO at transplant is a significant risk factor for death after transplantation [2]. Studies by a number of investigators have also confirmed greater mortality in pediatrics patients requiring mechanical assistance with ECMO [44–47] although an intermediate survival as great as 50% can be achieved. In the PHTS experience reported by Blume et al. [48] survival while waiting in patients on assist devices, excluding ECMO, is no difference is no different from other Status 1 patients (Fig. 4). Risk factors for death while waiting in the multivariable analysis were female gender, congenital heart disease, and earlier year of implantation. From this study it was also clear patients with longer term devices (Thoratec, Heartmate, Novacor, EXCOR) had better pre-transplant outcomes that
those with short term support (Abiomed BVS 5000, Medtronic Bio-Pump). The latter are more commonly employed in smaller children since most devices designed for chronic implantation are for patients of adult size. Survival after transplant in patients on mechanical assist devices [48], again not including ECMO, appears equivalent to other Status 1 patients not requiring device support. Stiller [49] recently reported a survival of 72% after transplantation at one year following bridge to transplant with the Berlin Heart pneumatic extracorporeal ventricular assist device. Multi-center studies in the United States are now underway to determine the utility of the Berlin Heart EXCOR as a bridge to transplant and post transplant survival of patients supported with this device. Good survival after transplantation in children and adolescents has also been reported using the DeBakey axial flow left ventricular assist device as a bridge to transplant [50]. The impact of the Berlin Heart and other mechanical assist devices on survival while waiting and after transplant is yet to be determined in large studies in children. To summarize, survival after transplantation in patients on ECMO is inferior to other patients transplanted as Status 1. However, from the PHTS analysis reported by Blume et al. [48], it is clear that those patients bridged to transplantation with mechanical devices designed for ventricular support do well with outcomes after transplantation equal to other Status 1 patients. Further developments await the results of the NIH funded INTERMACS registry and progress with devices designed specifically for the pediatric patient. 9. High panel reactive antibodies An important group of patients with congenital heart disease with or without device support is the patient with elevated panel reactive antibodies. Some patients have elevated antibodies to HLA antigens due to prior exposure to homograft material, blood products, or assist devices. A number of studies have demonstrated increased risk of rejection and death in this group of patients although interpretation of the literature is difficult due to differing methodologies for measuring Class I and Class II HLA antibodies [51–55]. While small series and case reports extol the potential benefit of measures to decrease circulating donor specific antibodies, such as gamma globulin infusion, plasmapheresis, and rituximab infusion the beneficial effect of these interventions on long-term survival remain to be determined. 10. Summary
Fig. 4. Actuarial survival of Status 1 patients with and without VAD support compared to Status 2 patients. There was no significant difference in the posttransplant survival between patients on VAD support and those who were not. (used with permission, Circulation).
Long term survival in children remains disappointing for those transplanted at least a decade ago. Clearly infant recipients have a survival advantage perhaps due to a relative degree of tolerance. Despite discouraging late survival estimates based on historical experience, early and intermediate survival is improving in recent studies at individual institutions and from the ISHLT registry and PHTS study group. This improving survival will probably result in improved long term survival in future years. Development of new strategies for immunosuppression, particularly those aimed at reducing graft loss from chronic rejection, may also significantly improve long term survival. Tailoring therapy
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to those who are at high risk, including those with high risk due to elevated PRA and those with other risk factors, such as high risk groups identified by high risk polymorphisms, may improve long term survival. References [1] Kantrowitz A, Haller JD, Joos H, Cerruti MM, Carstensen HE. Transplantation of the heart in an infant and an adult. Am J Cardiol 1968;22:782–90. [2] Boucek MM, Aurora P, Edwards LB, et al. Registry of the International Society for Heart and Lung Transplantation: Tenth Official Pediatric Heart Transplantation Report—2007. J Heart Lung Transplant 2007;26:796–807. [3] Bailey LL, Razzouk AJ, Wang N, Sciolaro CM, Chiavarelli M. Bless the babies; one hundred fifteen late survivors of heart transplantation during the first year of life. J Thorac Cardiovasc Surg 1993;105:805–15. [4] Canter CE, Moorhead S, Huddleston CB, Spray TL. Restrictive atrial communication as a determinant of outcome of cardiac transplantation for hypoplastic left heart syndrome. Circulation 1993;88:II–456–II-460. [5] Merrill WH, Frist WH, Stewart JR, et al. Heart transplantation in children. Ann Surg 1991;213:393–8. [6] Backer CL, Zales VR, Idriss FS, et al. Heart transplantation in neonates and in children. J Heart Lung Transplant 1992;11:311–9. [7] Bailey LL, Wood M, Razzouk A, Van Arsdel G, Gundry S. Heart Transplantation during the first 12 years of life. Arch Surg 1989;124:1221–6. [8] Armitage JM, Fricker FJ, del Nido P, Starzl TE, Hardesty RL, Griffith BP. A decade (1982–1992) of pediatric cardiac transplantation and the impact of FK506 immunosuppression. J Thorac Cardiovasc Surg 1993;105:464–72. [9] Radley-Smith RC, Yacoub MH. Long-term results of pediatric heart transplantation. J Heart Lung Transplant 1992;11:s227–81. [10] Baum D, Bernstein D, Starnes VA, et al. Pediatric heart transplantation at Stanford: results of a 15-year experience. Pediatrics 1991;88:203–14. [11] Starnes VA, Bernstein D, Oyer PE, et al. Heart transplantation in children. J Heart Lung Transplant 1989;8:20–6. [12] Slaughter MS, Braunlin E, Bolman RM, Molina JE, Shumway SJ. Pediatric heart transplantation: results of 2- and 5-year follow-up. J Heart Lung Transplant 1992;11:311–9. [13] Turrentine MW, Kesler KA, Caldwell R, et al. Cardiac transplantation in infants and children. Ann Thorac Surg 1994;57:546–54. [14] Razzouk AJ, Chinnock RE, Gundry SR, et al. Transplantation as a primary treatment for hypoplastic left heart syndrome: intermediate-term results. Ann Thorac Surg 1996;62:1–8. [15] Webber SA. 15 years of pediatric heart transplantation at the University of Pittsburgh: lessons learned and future prospects. Pediatr Transplant 1997;1:8–21. [16] Chiavarelli M, Gundry SR, Razzouk AJ, Bailey LL. Cardiac transplantation for infants with hypoplastic left heart syndrome. JAMA 1993;270:2944–7. [17] Canter CE, Moorhead S, Saffitz JE. Steroid withdrawal in the pediatric heart transplant recipient initially treated with triple immunosuppression. J Heart Lung Transplant 1994;13:74–80. [18] Morrow WR, Frazier EA, Naftel DC. Survival after listing for cardiac transplantation in children. Prog Pediatr Cardiol 2000;11:99–105. [19] WR Morrow, R Chinnock: Survival After Heart Transplantation. pg. 417–426 in “Pediatric Solid Organ Transplantation” Ed. Tejani, Harmon, and Fine. Munksgaard, in press. Blackwell. [20] Shaddy RE, Naftel DC, Kirklin JK. Outcome of cardiac transplantation in children: survival in a contemporary multi-institutional experience. Circulation 1996;94(suppl II):II–69–73. [21] Pahl E, Naftel DC, Canter CE, et al. Death after rejection with severe hemodynamic compromise in pediatric recipients: a multi-institutional study. J Heart Lung Transplant 2001;20:279–87. [22] Hsu DT, Naftel DC, Webber SA, et al. Lessons learned from the pediatric heart transplant study. Congenit Heart Dis 2006;1:54–62. [23] Lamour JM, Kanter KR, Naftel DC, et al. The effect of age, diagnosis and previous surgery in 488 children and adults who undergo heart transplantation for congenital heart disease. J Am Coll Cardiol 2005;45:322A.
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[24] Hsu DT, Quaegebeur JM, Michler RE, et al. Heart transplantation in children with congenital heart disease. J Am Coll Cardiol 1995;26:743–9. [25] Canter C, Naftel DC, Caldwell R, et al. Survival and risk factors for death after cardiac transplantation in infants: a multi-institutional study. Circulation 1997;96:227–31. [26] Sigfusson G, Fricker FJ, Bernstein D, et al. Long-term survivors of pediatric heart transplantation: a multicenter report of sixty-eight children who have survived longer than five years. J Pediatr 1997;130:862–71. [27] R Chinnock. Pediatric Transplant Primer, 2nd Edition, in press. [28] Webber SA, Naftel DC, Parker J, et al. Late rejection greater than 1 year after pediatric heart transplantation: an ominous finding. [abstract)J Heart Lung Transplant 1999;18:69. [29] Frazier EA, Naftel DC, Canter CE, et al. Death after cardiac transplantation in children: who dies, when, and why. J Heart Lung Transplant 1999;18:69–70. [30] Pahl E, Naftel DC, Kuhn MA. The impact and outcome of transplant coronary artery disease in a pediatric population: a 9-year multiinstitutional study. J Heart Lung Transplant 2005;24:645–51. [31] Hathout E, Beeson WL, Kuhn M, et al. Cardiac allograft vasculopathy in the pediatric heart transplant recipients. Transpl Int 2006;19:184–9. [32] Webber SA, Naftel DC, Fricker FJ, et al. Lymphoproliferative disorders after paediatric heart transplantation: a multi-institutional study. Lancet 2006;367:233–9. [33] West LJ, Pollock-Barzu SM, Dipchand AI, et al. ABO-incompatible heart transplantation in infants. N Engl J Med 2001;344(11):793–800. [34] West LJ, Karamlou T, Dipchand AI, Pollock-BarZiv SM, Coles JG, McCrindle BW. Impact on outcomes after listing and transplantation, of a strategy to accept ABO blood group-incompatible donor hearts for neonates and infants. J Thorac Cardiovasc Surg 2006;131:455–61. [35] Morrow WR, Parker JG, Naftel DC, et al. Adjunctive mycophenolate vs. azathioprine for prevention of rejection in pediatric heart transplant recipients. J Heart Lung Transplant 2005;24(2S):S113. [36] Addonizio LJ, Zangwill SD, Rosenthal DN, et al. Have changes in UNOS status system improved allocation in pediatric heart recipients? J Heart Lung Transplant 2005;24(2S):S64. [37] Kirklin JK, Naftel DC, Caldwell RL, et al. Should status II patients be removed from the pediatric heart transplant waiting list? A multiinstitutional study. J Heart Lung Transplant 2006;25:271–5. [38] Girnita DM, Webber SA, Ferrell R, et al. Disparate distribution of 16 candidate single nucleotide polymorphisms among racial and ethnic groups of pediatric heart transplant patients. Transplantation 2006;12:1774–80. [39] Girnita DM, Brooks MM, Webber SA, et al. Genetic polymorphisms impact the risk of acute rejection in pediatric heart transplantation: a multiinstitutional study. Transplantation 2008;85:1632–9. [40] Bernstein D, Naftel DC, Hsu DT, et al. Outcome of listing for cardiac transplantation for failed Fontan: a multi-institutional study. Circulation 2006;114:273–80. [41] Carey JA, Hamilton JR, Hilton CJ, et al. Orthotopic cardiac transplantation for the failing Fontan circulation. Eur J Cardiothorac Surg 1999;47:47–56. [42] Michielon G, Parisi F, Di Carlo D, et al. Orthotopic heart transplantation for failed single ventricle physiology. Eur J Cardiothorac Surg 2003;24:502–10. [43] A Gamba, M Merio, R Fiocchi, et al. Heart transplantation in patients with previous Fontan operations. J Thorac Cardiovasc Surg 127(2):555–562. [44] Del Nido P, Armitage JM, Fricker FJ, et al. Extracorporeal membrane oxygenation support as a bridge to pediatric heart transplantation. Circulation 1994;90:66–9. [45] Frazier EA, Faulkner SC, Seib PM, Harrell JE, Van Devanter SH, Fasules JW. Prolonged ECLS for bridging to transplant: technical and mechanical considerations. Perfusion 1997;12:93–8. [46] Fiser WP, Yetman AT, Gunselman RJ, et al. Pediatric arteriovenous extracorporeal membrane oxygenation (ECMO) as a bridge to cardiac transplantation. J Heart Lung Transplant 2003;22(7):770–7. [47] Gajarski RJ, Mosca RS, Ohye RG, et al. Use of extracorporeal life support as a bridge to pediatric cardiac transplantation. J Heart Lung Transplant 2003;22(1):28–34. [48] Blume ED, Naftel DC, Bastardi H, et al. Outcome of children bridged to transplantation with ventricular assist devices. Circulation 2006;113:2313–9.
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[49] Stiller B, Hetzer R, Weng Y, et al. Heart transplantation in children after mechanical circulatory support with pulsatile pneumatic assist device. J Heart Lung Transplant 2003;22:1201–8. [50] Goldstein DJ. Worldwide experience with the MicroMed Debakey Ventricular Assist Device as a bridge to transplantation. Circulation 2003;108(suppl II):II–272–II-277. [51] Wright EJ, Fiser WP, Edens RE, et al. Cardiac transplant outcomes in pediatric patients with pre-formed antihuman leukocyte antigen antibodies and/or positive retrospective crossmatch. J Heart Lung Transplant 2007;26:1163–9. [52] Ratkovec RM, Hammond EH, O'Connell JB, et al. Outcome of cardiac transplant recipients with a positive donor-specific crossmatch—preliminary results with plasmapheresis. Transplantation 1992;54:651–5.
[53] Jacobs JP, Quintessenza JA, Boucek RJ, et al. Pediatric cardiac transplantation in children with high panel reactive antibody. Ann Thorac Surg 2004;78:1703–9. [54] Bishay ES, Cook DJ, El Fettouh H, et al. The impact of HLA sensitization and donor cause of death in heart transplantation. Transplantation 2000;70:220–2. [55] Holt DB, Lublin DM, Phelan DL, et al. Mortality and morbidity in presensitized pediatric heart transplant recipients with a positive donor crossmatch utilizing peri-operative plasmapheresis and cytolytic therapy. J Heart Lung Transplant 2007;26:876–82.
Outcomes following heart transplantation in children W. Robert Morrow ⁎ Division of Pediatric Cardiology, Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, AR, United States
Abstract After nearly 30 years of heart transplantation in children, following the introduction of cyclosporine, it is clear that early and intermediate survival following transplantation is good. Actuarial survival at one year, 5 years, 10 years are 85%, 75%, and 64% respectively. Fifteen year actuarial survival in the ISHLT Registry is approximately 47%. Naturally, late survival reflects early experience with transplantation in children and a worst case scenario. Recent studies show that survival is improving owing almost entirely to reduced early mortality after transplant. Survival at five years in the current era, 2001–2005, is 77% compared to 72% for the era 1993–2000. Multiple factors may account for this reduced early mortality including better peri-operative management, improved immunosuppression but also better case selection and earlier referral. However, despite improving results and reduced early mortality, there is an ongoing constant phase of mortality, approximately 3% per year, resulting in decreasing survival with time. This ongoing risk of death has persisted but may be less in the current era due to improvements in immunosuppression. Important differences in survival exist between patients of different age at transplant. While early survival in infants is less than in older children, late survival and overall survival is better. For those infants surviving at least one year after transplant subsequent ten year survival is approximately 80% compared to 70% for children 1–10 years of age and 60% for children 11–17 years of age. Of note, the constant hazard for death appears to be less the younger the infant is at transplant, compared to older children. This may represent a degree of conditional tolerance in the youngest infant. Patients with congenital heart disease have good survival following transplant but less than patients with cardiomyopathy or myocarditis. However, for patients with failed Fontan palliation for single ventricle survival is comparable to other patients with congenital heart disease. Outcomes for patients requiring mechanical support are poor for patients bridged to transplant with ECMO but are equivalent to other Status 1 patients for those on left ventricular assist devices (Thoratec, HeartMate, Abiomed, etc.). Outcomes of bridge to transplant with Berlin EXCOR appear to be superior to ECMO but a multi-center study is underway. Despite discouraging late survival estimates based on historical experience, improving survival in more recent eras will probably result in improved long term survival in future years. Development of new strategies for immunosuppression, particularly those aimed at reducing graft loss from chronic rejection, may also significantly improve long term survival. In addition, tailoring therapy to those who are at high risk, including those with high risk due to elevated PRA and those with other risk factors may improve long term survival. © 2008 Published by Elsevier Ireland Ltd. Keywords: Heart transplant; Cardiac; Heart disease; Antibodies
1. Introduction Although the first heart transplant in a child was reported by Kantrowitz in 1968 [1], widespread use of transplantation for lethal heart disease in children only became practical following ⁎ Division of Cardiology, Arkansas Children's Hospital, 800 Marshall Street, Little Rock, AR 72202, United States. Tel.: +1 501 320 1479; fax: +1 501 320 3667. E-mail address: [email protected]. 1058-9813/$ - see front matter © 2008 Published by Elsevier Ireland Ltd. doi:10.1016/j.ppedcard.2008.10.005
the introduction of cyclosporine in the early 1980's. The registry of the International Society for Heart and Lung Transplantation (ISHLT) records 6979 cardiac transplant procedures in children ranging from 11 transplants in 1982 to a peak of 403 in 2005 [2]. Fortunately, with improvement of preoperative assessment, patient selection, post-operative care, and immunosuppression, survival following heart transplantation in the pediatric patient is good. Early, intermediate, and late survival has been reported from many institutions, multiinstitutional studies, and registries [2–19]. Published experience
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demonstrates varying survival by center, patient age at transplant, diagnosis at listing and era of transplant in addition to a number of other pre-transplant risk factors. In addition to mortality after transplantation, mortality for potential transplant recipients is significant prior to transplantation. However, as experience has increased survival both before and after transplantation has improved. While there are many potential outcomes to consider, including patient survival, graft survival, developmental and social outcome, and others, this discussion will be confined to patient survival. Survival of listing and survival inclusive of pre-transplant and post-transplant mortality has been reviewed elsewhere [18,19]. Here we will also limit our review to survival of children after transplantation only, with an emphasis on late outcomes. We will also focus on outcomes in specific age groups, pre-transplant diagnoses, and special circumstances. An important general feature of survival following transplantation is that there is a consistent early phase hazard for mortality followed by a constant hazard. This means that early after transplantation the risk of death is highest (an exponential function) but short lived and is followed by a risk of mortality that represents a constant annual risk of death (linear slope). The continuing constant phase of mortality produces an inexorable decline in survival with each subsequent year post-transplant. 2. Early and intermediate term survival in children A number of institutions have reported excellent early and intermediate post-transplant survival in both infants and children [3–17] following cardiac transplantation. It is impos-
sible to compare results between individual centers and multicenter reports because of differences in recipient selection, era of transplant, evolving surgical experience, and differences in immunosuppressive and surveillance regimens. In most single center reports statistical analysis of risk factors for death, if it is performed at all, is limited to univariate techniques because of small numbers. While the early outcomes following transplantation in children had been reported by the ISHLT Registry, these initial reports lacked complete data submission and meaningful risk factor analysis. For this reason, the Pediatric Heart Transplant Study Group (PHTS), which began data collection in 1993, undertook an analysis of outcomes of transplantation of early survival after transplantation in infants and children. Shaddy et al., reported this initial PHTS survival experience and risk factor analysis among 191 children older than one year of age who underwent transplantation [20]. Actuarial survival after transplant at 1 month was 93% and was 82% at one year. By multivariable analysis the major risk factor for death was the need for assist devices at the time of transplant (p = 0.02). Nonetheless, overall survival after transplantation among Status 1 and Status 2 patients was not different. Younger age in this group of patients over one year of age at transplant was a significant risk factor for death in the multi-variable analysis. Patients in the 1–5 year age range had a one year actuarial survival of 74% compared to 86% for patients over five years of age at transplant. These single center reports, the initial ISHLT registry reports, and early PHTS experience were all published in the early 1990's. Thus they represent the earliest experience with pediatric transplantation in the cyclosporine era. Subsequent
Fig. 1. Actuarial survival in the most current PHTS analysis among 1978 patients undergoing primary heart transplantation. A short early phase hazard for mortality is seen prior to 6 months post transplant with an ongoing constant hazard for death thereafter. Survival is 85% at one year, 75% at five years, and 64% at ten years.
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reports by the PHTS [18–19,21–24] have shown five year survival following transplantation of approximately 75%. In the most recent analysis of the PHTS data including 1978 patients undergoing transplantation, 38% were less than one year, 37% were between one and 12 years, and 25% were greater than 12 years of age at transplant. 69% of patients were Status 1 or Status 1A. Overall actuarial survival after transplantation for all age groups was 85% at one year and 75% at five years (Fig. 1). Neither urgency status at transplant or ischemic time affected five year survival. This is in keeping with more recent registry reports of the ISHLT database although 5 year survival in the most recent registry report ranges from approximately 68% depending, possibly due to the inclusion of patients transplanted in the decade before the PHTS. 3. Early and intermediate survival in infants Bailey et al. [3] at Loma Linda pioneered infant transplantation in the early days of the cyclosporine era. Survival after transplantation in the Loma Linda experience was initially 85% at one year and 80% at five years in 139 infants who underwent heart transplantation for a variety of diagnoses. In a group with HLHS survival after transplantation was similar with a five-year actuarial survival of 74% [7,14,16]. By far most mortality was early, even peri-operative, and was the result of early graft failure due to primary graft dysfunction, pulmonary hypertension, or technical factors. Others have also reported excellent survival in this age group as well [4,17]. Canter et al. [25] examined early survival after heart transplantation in the PHTS experience among infants less that one year at transplant. The majority of infants (66%) had hypoplastic left heart syndrome. Survival was less than in older children with 70% of infants surviving at one year compared to 82% in children older than one year. The peak hazard for death was within the first month post transplant (early phase) with 16% of patients dying in this interval. Risk factors for death included a history of previous sternotomy (p = 0.0003) and a donor cause of death other than closed head trauma. Previous history of sternotomy in this age group implies a very recent but failed attempt at repair and, therefore, represents a particularly high risk group of patients. Most deaths early after transplantation occurred as a result of graft failure or pulmonary hypertension. When combined these two causes of death accounted for 75% of deaths in the infant age group. In the most recent PHTS analysis (unpublished) survival among infants less than 6 months of age at transplant was 82% at one year and 66% at 10 years post transplant compared to older children where one year survival is 88% and 10 year survival is 55%. This observation of greater early mortality but less intermediate and late mortality is important and has been confirmed by other centers as well as analysis of the ISHLT Registry data. 4. Late survival For the purposes of this report late survival is defined as survival after 10 years following transplantation. While this may be an acceptable definition for adults undergoing transplantation, the
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reasonable expectation of greater longevity in children undergoing transplantation should provoke a sober look at survival at greater than 15 to 20 years. Data are only now becoming available for such long term survival at 15 to 20 years and are largely provided by the ISHLT registry report and single institution reports of programs with early experience with heart transplantation in children. The obvious limitation of such data is that it is from the earliest era in transplantation during a steep clinical learning phase. Late survival at Stanford was low with a reported 10 year survival of 60% [10,11]. Importantly, the Stanford program pioneered heart transplantation in children and many patients in this series underwent transplantation prior to the cyclosporin era. Sigfusson et al. [26] analyzed “conditional” survival from the experience of three institutions with long term experience. In that analysis actuarial survival of patients who had survived at least five years was 80% at ten years post transplant but 67% at 15 years emphasizing ongoing mortality, primarily due to acute rejection and graft atherosclerosis. Again, only patients who had survived at least five years were included in the analysis and, therefore, these data do not reflect overall 10 and 15 year survival. Webber reported a 10 year survival of approximately 45% in a cohort of 37 patients transplanted between 1982 and 1989 [15]. However, in this same cohort five year survival was approximately 50%, less than what has been achieved at other institutions in more recent cohorts. In the same report Webber notes a much improved contemporary four year survival of greater than 90% implying the potential for much improved long term survival of this more recent cohort. Fifteen year actuarial survival for the earliest cohort of patients in the ISHLT registry (1982–1988) is 40%. However, for this same cohort actuarial survival at 5 years was 58% whereas the actuarial survival at 5 years in a more current era (1999–2003) is 70%. Most of this improving survival benefit is seen in the six months following transplant, indeed within the first month. Risk factors for death after transplantation at one year were need for a ventilator prior to transplant and hospitalization prior to transplant, both indications of a decompensated, severely ill patient. Interestingly, neither donor ischemic time or transplant center volume were risk factors for death after transplantation, in contrast to previous analyses of the ISHLT registry data. The ISHLT registry report gives a 15 year actuarial survival of approximately 40% for all ages [2]. However, if a recipient survives at least five years after transplant subsequent conditional 15 year survival is 65% (after five years post transplant). For infants who survive at least five years conditional survival is predicted to be 80%. The PHTS experience [19,22] confirms the presence of an ongoing constant phase of mortality (Fig. 1) which could result in a fifteen year survival in the range of 45%. However, it is very likely that improvement in early survival described above will translate to better long term survival for patients transplanted in the current era. The continuing occurrence of late rejection [28], rejection deaths [29], graft atherosclerosis [29–31], and lymphoproliferative disease [32] accounts for the continued intermediate and late mortality and raise concern about the ultimate fate of children who have undergone cardiac
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transplantation. The most recent analysis of the PHTS data (unpublished) suggests improving survival in the constant phase (p = 0.02) for the era after 1997 although the actual effect this reduction in mortality is small. 5. Late survival in infants As noted above, the Loma Linda experience [19,27] and analysis of the PHTS data have demonstrated a better long-term survival in neonates with HLHS compared to older infants. From 1985 through 2004, 282 infants underwent transplantation at Loma Linda [19,28]. Patient survival among newborns (less than 30 days at transplant) was77% at 10 years and 71% at 15 years compared to 54% at 10 years and 48% at 15 years for infants (p = 0.0029). Actuarial graft survival, including graft loss in patients who underwent re-transplantation, was 71% at 10 yrs, 62% at 15 yrs for newborns and 47% at 10 yrs, 40% at 15 yrs for infants (p = 0.002). Younger age at transplant was associated with a decreased risk of graft loss. Similarly, in a recent analysis of the PHTS data (2004), one year survival in infants less than 6 months at transplant was 80% and was 70% at 9 years compared to older children where one year survival was 87% and 5 year survival was 66%. Thus patients transplanted as newborns fared better than infants and infants fared better than older children. In the analysis of the Loma Linda experience, Chinnock [28] examined the contribution of immunological factors, rejection history and graft loss due to rejection or post-transplant coronary artery disease. Long-term actuarial freedom from rejection was 23% (10 yrs and above) for infants versus 8%
(10 yrs and above) for newborns (p = 0.003). However, actuarial freedom from graft loss due to rejection or post-transplant coronary artery disease was 59% at15 yrs for infants compared to 84% at 10 yrs, 78% at 15 yrs for newborns (p = 0.009). In the most recent analysis of the ISHLT Registry data [2] there appears to be a clear survival advantage in children transplanted at less than 1 year of age compared to older children. While the early phase risk of death was greater than older children the constant hazard for death appeared to be less. This was best seen in the analysis of conditional survival. For infants less than one year of age surviving at least one year after transplant the subsequent 15 year survival was 67% compared to 55% for children 1–10 years of age. Likewise, for the same groups surviving at least 5 years the subsequent 10 year survival was 80% for infants transplanted at less than a year of age and 67% for children 1–10 years of age at transplant. The reasons for better long-term survival in infants are multifactorial. However, earlier age at transplant is associated with improved patient and graft survival and is likely related to immunologic factors. This may have implications for use of ABO-incompatible donors. A strategy which uses a prolonged waiting time before proceeding to accepting an ABO incompatible donor could potentially disadvantage the neonatal recipient. West et al. [33,34] reported their experience with ABO incompatible heart transplant in neonates and infants. Overall survival was 80 percent. Interestingly, these infants did not experience hyperacute rejection and the only deaths which occurred were not related to ABO incompatibility. Most patients did not develop antibody to donor blood group although two did without apparent graft damage.
Fig. 2. Actuarial survival in pediatric heart transplant recipients (n = 1978) stratified by era of transplantation. Survival is significantly better after 1995 compared to before. Improvement in survival is seen early after transplantation and in the era beginning in 1997 for the constant hazard for death (p = 0.02).
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The apparent long term survival advantage strongly argues for a strategy of primary transplantation for infants who have poor medical or surgical options. Of great interest is the apparent divergence in the constant phase hazard for death in neonates and infants from older children. It is important to remember, that the patients with the longest survival (or late mortality) were transplanted in an era which preceded widespread use of newer immunosuppressive regimens including tacrolimus, mycophenolate, sirolimus, and humanized or chimeric IL-2 receptor antibodies and were based primarily on triple immunosuppression with cyclosporin, azathioprine, and corticosteroids. Recent evidence suggests that combination therapy with these newer agents may significantly improve early and intermediate survival [35]. It is unclear at this point whether these interventions will alter the slope, or rate of death after transplant in the constant phase. 6. Improving survival — an era effect? Several recent publications from the PHTS experience have reported an improving overall survival [18–19,22]. Essentially, survival in patients at PHTS centers was significantly better after 1995 compared to prior to that time. In the most recent analysis (Fig. 2), 5 year survival was 72% for the era 1993– 2000 compared to 77% for the era 2001–2005 (p = 0.01). At this point, implementation of the new UNOS urgency status designation in January of 2001 does not appear to have had any impact on post-transplant survival [36,37]. Similar outcomes have been reported in the most recent ISHLT Registry report [2]. Survival was significantly better after 1990 than before and better after 1995 than in the era from 1990–1994. A close examination of the actuarial survival curves in the ISHLT and PHTS studies demonstrates that the greatest improvement in survival occurs within months following transplant while a constant hazard for death following transplant begins within 6 months of transplant. In fact, most of the improvement in survival can be accounted for by decreased early mortality. Previous analyses of the ISHLT data and the PHTS data have indicated that the constant hazard for death has remained unchanged despite improvements in early survival. However, the most recent analysis of the PHTS data (unpublished) has shown improving survival in the constant phase (Fig. 2). There are many potential reasons for improved survival in the early phase after transplantation. Certainly pre and post operative management has improved including use of nitric oxide and ECMO for rescuing patients with pulmonary hypertension and right ventricular failure. But other factors may play a significant role as well including earlier referral for transplantation, better case selection, fewer low volume centers, and less highly toxic induction regimens. While not playing a role in reduced early mortality to date, elucidation of specific genetic risk factors in the form of polymorphisms which are associated with increased risk of rejection and/or altered metabolism of immunosuppressive agents may allow better tailoring of maintenance immunosuppression to specific patient risk [38,39].
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7. Survival after transplantation for congenital heart disease Patients with congenital heart disease account for roughly half of all pediatric patients undergoing heart transplantation [2] depending on the age of the patient. Outcomes for infants with hypoplastic left heart syndrome are summarized above. Survival in the early experience with patients with other congenital heart defects initially appeared to be lower than survival in patients with acquired heart disease [8,9]. More recent experience [2,22–24] suggests that there may be in fact a difference in survival among children who undergo heart transplantation for a primary indication of congenital heart disease when compared to those without congenital heart disease. A pre-transplant diagnosis of congenital heart disease was not an independent risk factor for death in the initial PHTS experience. However, if one specifically excludes infants with hypoplastic left heart syndrome, subsequent analysis demonstrates that early survival in patients with cardiomyopathy or myocarditis is superior to survival in patients with congenital heart disease [23]. A special group of patients are those with a failed Fontan repair for single ventricle. These patients undergo transplantation for a variety of indications, the most common being protein losing enteropathy or “right heart failure”. Transplantation in this group can be performed with good survival [40–43] and with anticipated improvement in protein losing enteropathy. In the series reported by Bernstein [40] from the PHTS, actuarial survival after transplant was 77% at one year and 67% at five years (Fig. 3). This survival was no different from patients with congenital heart disease older than one year of age at transplant (excludes primary transplant in patients with HLHS) but was lower than those with cardiomyopathy. Importantly, time since repair in this and other lesions seems to be important in predicting survival. Transplantation performed early after repair in an attempt to salvage patients is more likely to result in death than transplantation many years after repair. In contrast to all
Fig. 3. Actuarial survival after transplantation in pediatric patients undergoing transplantation for failed Fontan procedure (40). There is no significant difference in survival after transplant in patients with prior Fontan palliation compared to patients with other repaired congenital heart defects. (used with permission, Circulation).
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other diagnostic groups, the most common cause of death in patients transplanted for failed Fontan is infection. Patients with protein losing enteropathy who have severe nutritional deficiency and wasting are at greater risk of death from infection after transplantation due to immunodeficiency and poor healing associated with longstanding malnutrition. Clearly, appropriate patient selection is key to successful surgical repair and some patients with single ventricle physiology are better served by primary transplantation rather than attempts at surgical palliation with Fontan repair or revision of previous Fontan [42,43]. For survivors, resolution of protein losing enteropathy is the rule but many have persistent hypoalbuminemia and protein loss for months following transplantation [38]. 8. Impact of mechanical device support on survival In the Pittsburgh experience [15] an important risk factor for death in Status 1 patients was the requirement for a mechanical assist device prior to transplantation. Until recently, in the pediatric age group this usually meant the use of extracorporeal membrane oxygenation (ECMO) although a variety of left ventricular assist devices are used including centrifugal pumps functioning as left ventricular assist devices as well as Thoratec and Heartmate left ventricular assist devices in adolescents. The most recent ISHLT registry analysis demonstrates that ECMO at transplant is a significant risk factor for death after transplantation [2]. Studies by a number of investigators have also confirmed greater mortality in pediatrics patients requiring mechanical assistance with ECMO [44–47] although an intermediate survival as great as 50% can be achieved. In the PHTS experience reported by Blume et al. [48] survival while waiting in patients on assist devices, excluding ECMO, is no difference is no different from other Status 1 patients (Fig. 4). Risk factors for death while waiting in the multivariable analysis were female gender, congenital heart disease, and earlier year of implantation. From this study it was also clear patients with longer term devices (Thoratec, Heartmate, Novacor, EXCOR) had better pre-transplant outcomes that
those with short term support (Abiomed BVS 5000, Medtronic Bio-Pump). The latter are more commonly employed in smaller children since most devices designed for chronic implantation are for patients of adult size. Survival after transplant in patients on mechanical assist devices [48], again not including ECMO, appears equivalent to other Status 1 patients not requiring device support. Stiller [49] recently reported a survival of 72% after transplantation at one year following bridge to transplant with the Berlin Heart pneumatic extracorporeal ventricular assist device. Multi-center studies in the United States are now underway to determine the utility of the Berlin Heart EXCOR as a bridge to transplant and post transplant survival of patients supported with this device. Good survival after transplantation in children and adolescents has also been reported using the DeBakey axial flow left ventricular assist device as a bridge to transplant [50]. The impact of the Berlin Heart and other mechanical assist devices on survival while waiting and after transplant is yet to be determined in large studies in children. To summarize, survival after transplantation in patients on ECMO is inferior to other patients transplanted as Status 1. However, from the PHTS analysis reported by Blume et al. [48], it is clear that those patients bridged to transplantation with mechanical devices designed for ventricular support do well with outcomes after transplantation equal to other Status 1 patients. Further developments await the results of the NIH funded INTERMACS registry and progress with devices designed specifically for the pediatric patient. 9. High panel reactive antibodies An important group of patients with congenital heart disease with or without device support is the patient with elevated panel reactive antibodies. Some patients have elevated antibodies to HLA antigens due to prior exposure to homograft material, blood products, or assist devices. A number of studies have demonstrated increased risk of rejection and death in this group of patients although interpretation of the literature is difficult due to differing methodologies for measuring Class I and Class II HLA antibodies [51–55]. While small series and case reports extol the potential benefit of measures to decrease circulating donor specific antibodies, such as gamma globulin infusion, plasmapheresis, and rituximab infusion the beneficial effect of these interventions on long-term survival remain to be determined. 10. Summary
Fig. 4. Actuarial survival of Status 1 patients with and without VAD support compared to Status 2 patients. There was no significant difference in the posttransplant survival between patients on VAD support and those who were not. (used with permission, Circulation).
Long term survival in children remains disappointing for those transplanted at least a decade ago. Clearly infant recipients have a survival advantage perhaps due to a relative degree of tolerance. Despite discouraging late survival estimates based on historical experience, early and intermediate survival is improving in recent studies at individual institutions and from the ISHLT registry and PHTS study group. This improving survival will probably result in improved long term survival in future years. Development of new strategies for immunosuppression, particularly those aimed at reducing graft loss from chronic rejection, may also significantly improve long term survival. Tailoring therapy
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