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Ann Thorac Surg 2007;83:169-172
© 2007 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Infant Heart Transplantation Ten Years Later—Where Are They Now?

^a Department of Surgery, Washington University School of Medicine, St. Louis Children’s Hospital, St. Louis, Missouri
^b Department of Pediatrics, Washington University School of Medicine, St. Louis Children’s Hospital, St. Louis, Missouri

Accepted for publication August 4, 2006.

^_* Address correspondence to Dr Gandhi, 1 Children’s Place, Suite 5S 50, St. Louis, MO 63110 (Email: gandhis{at}wustl.edu).

Presented at the Fifty-second Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 10–12, 2005.

	Abstract

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BACKGROUND: Many uncertainties regarding the fate of children undergoing heart transplantation as infants were present when we and others embarked on this program. Although no truly long-term results are available, a significant cohort of children has now reached preteen and early teenage status. We reviewed our group of infants transplanted more than 10 years ago to assess survival and quality of life as they approach their teenage years.

METHODS: We retrospectively reviewed the medical records of all infant (younger than 6 months of age) heart transplant recipients, transplanted between 1988 and 1995, to ascertain survival statistics, incidence of complications, and current health status.

RESULTS: A total of 42 patients were identified. The majority of these underwent transplantation for hypoplastic left heart syndrome. Eleven patients have died, 4 early and 7 late. The actual survival at 10 years is 76%. Twenty-seven of the 31 long-term survivors attend regular school; 4 are in special education classes owing to developmental delay. Five patients take medication for attention-deficit disorder. Malignancies have been discovered in 5, and 1 died secondary to this. Six patients have significant renal insufficiency, 1 of whom has undergone renal transplantation. One patient has undergone retransplantation for coronary artery disease. One patient required reoperation for supravalvar aortic stenosis. Other general medical problems that are being treated include sleep apnea (n = 1), hypertension (n = 5), and recurrent pneumonias (n = 1).

CONCLUSIONS: Although these children require ongoing medical attention, including daily medications and regular follow-up visits, most have a satisfactory quality of life and behave much like normal children.

	Introduction

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The notion of cardiac transplantation in neonates was introduced in 1985 with the controversial implant of a baboon heart into "Baby Fae." [1] Subsequent to that, the Loma Linda group published the first three successful cardiac transplants using allografts for neonates, all of whom had hypoplastic left heart syndrome [2]. Many important issues of concern were unknown at that time, issues that might have significant implications on the health and well-being of these infants as they grow older. These included growth of the patient and the heart, the relative risk of rejection and infection in a group of individuals likely to have a variety of ordinary infections over the course of the first few years of life, the risk of coronary vasculopathy, and how these children might adapt to a normal environment involving family, school, and so forth given the complexity of medical therapy required after heart transplantation. Would these children live beyond a few years; would they reach adulthood and be able to be productive? The purpose of this review is to examine a cohort of patients who received a transplant during early infancy and are now more than 10 years after transplantation. Their quality of life will be assessed by examining the general medical condition of these children as well as the nature of their participation in school.

	Material and Methods

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A retrospective review of all children undergoing heart transplantation younger than the age of 6 months was performed. Only those undergoing transplantation before 1995 were included so that complete 10-year follow-up would be available for all survivors. Their medical records were reviewed, and telephone conversations with the parents were conducted. Forty-two patients were identified. The average age at transplant was 44 days (range, 4 to 143 days). Thirty-eight patients carried the diagnosis of hypoplastic left heart syndrome (HLHS), 2 had other complex congenital cardiac lesions not amenable to surgical reconstruction, and 2 had cardiomyopathies. Two patients with HLHS had undergone a Norwood procedure previously. Immunosuppression in this series was with cyclosporine, azathioprine (Imuran), and prednisone. Every effort was made to discontinue steroids within the first year after transplantation. Surveillance for rejection was through scheduled endomyocardial biopsies performed at 1, 2, and 4 weeks, then at every 3 months for 12 months, and annually thereafter. Evaluation for posttransplant coronary vasculopathy was through coronary angiography and intracoronary ultrasound [3]. Results are expressed as mean ± standard deviation. Washington University institutional review board approval was obtained, and a waiver was granted for patient and parental consent.

	Results

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Survival
There were 4 early deaths. Three of these were caused by graft failure and 1 was caused by sepsis after perforation of a duodenal ulcer. The 3 patients with graft failure were placed on extracorporeal membrane oxygenator support, but failed to wean from this. The causes of late death were pulmonary venoocclusive disease (n = 1), transplant coronary vasculopathy (n = 2), sudden death presumed to be rejection-related (n = 1), posttransplant lymphoproliferative disease (n = 1), and infection (n = 2). The patient who succumbed to pulmonary venoocclusive disease had presented with HLHS and a restrictive atrial septal defect treated initially with balloon atrial septostomy; he died 3 months after transplantation. The 10-year actual survival for these patients was 76% (Fig 1).

View larger version (7K): [in this window] [in a new window]   Fig 1. Ten-year actual survival curve.

Renal Function
Six patients suffer from significant renal insufficiency, defined as National Kidney Foundation stage 3 or above. One patient has been diagnosed with glomerulonephritis, the others are believed to be secondary to long-term use of calcineurin inhibitors. One of the patients had progressive renal insufficiency and has undergone kidney transplantation. The others have been stable and have not required dialysis.

Malignancies
Five children have developed malignancies. Four patients have acquired posttransplant lymphoproliferative disorder, 1 resulting in death. The remainder were treated successfully with chemotherapy and alterations in immunosuppression. One child was diagnosed with a hepatoblastoma.

Rejection
Rejection was diagnosed in 19 patients. Four of these patients had more than one episode of rejection. The majority of these rejection episodes occurred within the first 6 months after transplantation although four occurred more than 1 year later. One patient died of presumed acute rejection associated with sudden death; this was the only rejection episode associated with hemodynamic compromise and was the only one not confirmed histologically. All other episodes of rejection were well tolerated and treated with bolus steroids daily for 3 days.

Transplant Coronary Vasculopathy
Five patients were diagnosed with coronary artery disease. Two patients have died of this complication. Another patient required retransplantation approximately 1 year after the initial transplant. That patient is doing well and has no evidence of transplant coronary artery disease in his second graft. The other 2 patients have mild stable disease.

Neurologic Development
Formal testing of these patients was not performed. Four children attend special education classes because of developmental delay; the other 27 long-term survivors attend regular school and participate in physical education classes as well as other activities appropriate for age. Five patients currently take medication for the diagnosis of attention-deficit disorder.

Other Medical Concerns
One patient had supravalvar aortic stenosis 12 years after his original transplant and underwent surgical repair of this. One patient has sleep apnea. Five patients are being treated for hypertension, predominantly with calcium-channel blockers. Three patients have exhibited some form of acquired autoimmune disease. Another patient has had recurrent bouts of pneumonia as a result of both viral and bacterial causes.

	Comment

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Survival after heart transplantation depends on the avoidance of graft failure early on, prompt recognition and treatment of acute rejection, avoidance of serious infections, and avoidance of transplant coronary vasculopathy. No one could be certain of the long-term outcomes in children when programs for neonatal heart transplantation were initiated. However, the hope was for these children to survive to become adults, a lofty and perhaps somewhat unrealistic goal given results observed in older age groups. Adults undergoing heart transplantation have a survival of approximately 50% at 10 years after transplantation, the most common cause of late death being transplant coronary vasculopathy. The survival curve beyond 10 years continues on a steady downward trend [4]. In our cohort of infants, the survival at 10 years is 76%, and the survival curve appears relatively flat. This is very much like the survival curve published by a large registry [5].

Beyond survival, however, quality of life is an important issue. It is somewhat difficult to define precisely what to measure to get a handle on this. A common question posed by parents before any major cardiac procedure in a small infant is "Will my baby be able to live a normal life?" Life after heart transplantation cannot be interpreted as normal by any measure. There will be daily medications, regular visits to physicians, ongoing risks of infection, and side effects of medications that alter outward appearance. We looked at the general medical condition of the patient and a rather gross view of the overall neurologic status as reflected in school activity. We previously reported our results of somatic growth after transplantation; children generally grow along the 10th to 25th percentile in both height and weight [6].

Most of these infants were born with HLHS. Prior studies of infants with this diagnosis have shown a significant number with minor or major central nervous system anomalies present before any surgical procedure [7]. Other more recent studies have shown abnormalities on magnetic resonance imaging of the brain in infants with complex congenital heart disease before any operative intervention. More sophisticated studies of neurocognitive function of children undergoing transplantation during infancy have been published. These show that children with transplants perform at a slightly lower degree than normal children, although the differences were not profound [8]. Evaluation of the exercise capacity of children who underwent transplantation during infancy has shown a similar performance compared with otherwise normal children [9]. Not all of the children in our series of infants undergoing heart transplantation are normal, but there is reason to be optimistic about their ability to function as normal children within their families and peers at school.

The incidence of rejection is relatively low in this group of children after cardiac transplantation. Certainly the incidence of transplant coronary vasculopathy is much lower than that seen in adults, in which it is approximately 45% at 8 years after transplantation and is a major cause of death [4]. In our series we had an incidence of approximately 12% of our patients with coronary artery disease at 10 years of follow-up, similar to that published in the registry for the International Society for Heart and Lung Transplantation [5]. The reason for this lower incidence is unknown, but may be related to the lower incidence of rejection observed in younger children undergoing heart transplantation. We previously observed a lower incidence of acute and chronic rejection in infants undergoing lung transplantation as well [10]. This is presumably related to an immature host, as far as the immunologic system is concerned.

In summary, infants undergoing heart transplantation have excellent survival in intermediate follow-up. Neurodevelopmental abnormalities exist, but are similar to those seen with other serious congenital cardiac anomalies requiring treatment early in life. Currently, HLHS, which was the most common diagnosis in this series, is managed with staged surgical palliation. Heart transplantation, because of the severe shortage of available donor organs, is reserved for specific anatomic contraindications (such as severe pulmonary insufficiency) and for failed palliative surgery. Continued follow-up of both the transplanted and staged palliated patients will provide further insights into the long-term outcomes of heart transplantation in children.

	Discussion

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DR D. GLENN PENNINGTON (Johnson City, TN): Outstanding report. Infants actually have a much better 10-year survival than adults. Could you just tell us about the immunosuppressive protocol and were you able to withdraw steroids in these children and what about growth, et cetera?

DR GANDHI: The growth data have been previously published. They grow, on average, between the 10th and 25th percentile, and that growth is maintained throughout this 10-year follow-up. So that is not bad. The immunosuppression is pretty standard triple immunosuppression with steroids, a calcineurin inhibitor, and azathioprine. In the past, the calcineurin inhibitor was exclusively cyclosporine; now, some children are placed on cyclosporine and some given FK. I don’t know the exact answer in terms of how quickly they were weaned off steroids, but some of them have been weaned off steroids. Doctor Canter, our transplant cardiologist, would know the answer to that question better than I.

DR JOHN H. CALHOON (San Antonio, TX): It was a very nice presentation and incredibly great results. Do you know how many people were converted to FK from cyclosporine for gum hyperplasia, or was that an issue in this series? It is just something I have seen.

DR GANDHI: Several children have been converted to FK for a variety of reasons. I don’t know how many were converted specifically for gingival hyperplasia secondary to the use of cyclosporine.

DR JOHN W. HAMMON (Winston-Salem, NC): These are truly spectacular results and your group is to be congratulated. They are clearly better than adult heart transplant results and they are better than long-term Norwood results. The one question that I have is you didn’t tell us how many patients died while awaiting transplant, particularly the hypoplastic group.

DR GANDHI: That is a good question. The answer is about 15% to 20% mortality on the waiting list. Although the results are good, if you take into account the number of children that we lost on the waiting list, the results are probably comparable to Norwood results. And it should be stated that we no longer perform primary heart transplantation for hypoplastic left heart syndrome. The Norwood pathway is the strategy used because of the limited availability of donor organs and the waiting list mortality. I don’t know how primary transplantation today for hypoplastic left heart syndrome would compare to a contemporary Norwood strategy. I would fathom to guess that the Norwood results would probably be better.

DR THOMAS YEH (Dallas, TX): Congratulations on your excellent follow-up and analysis of your cohort. In view of the current thoughts on the immunologic privilege of infants undergoing ABO mismatched cardiac transplantation, I was wondering whether you have considered diminishing some of your immunosuppression in infants undergoing ABO matched transplantation, the idea being to decrease some of the morbidity of either infection or malignancy?

DR GANDHI: There is no question about that. Obviously we are dealing with an immature immunologic host. The survival and the rejection episodes are much more favorable than in adults, and I think that is the reason why. And the same can be said of our infant lung transplant population.

	References

Top Abstract Introduction Material and Methods Results Comment Discussion References

 

1. Bailey LL, Nehlsen-Cannarella SL, Concepcion W, Jolley WB. Baboon-to-human cardiac xenotransplantation in a neonate JAMA 1985;254:3321-3329.[Abstract/Free Full Text]
2. Bailey LL, Nehlsen-Cannarella SL, Doroshow RW, et al. Cardiac allotransplantation in newborns as therapy for hypoplastic left heart syndrome N Engl J Med 1986;315:949-951.[Medline]
3. Trulock EP, Edwards LB, Taylor DO, et al. Surveillance for transplant coronary artery disease in infant, child, and adolescent heart transplant recipients: an intravascular ultrasound study J Heart Lung Transplant 2006;25:921-927.[Medline]
4. Trulock EP, Edwards LB, Taylor DO, et al. The registry of the International Society for Heart and Lung Transplantation: Twenty-first official adult heart transplant report—2004 J Heart Lung Transplant 2004;23:804-815.[Medline]
5. Boucek MM, Edwards LB, Keck BM, et al. Registry for the International Society for Heart and Lung Transplantation: seventh official pediatric report—2004 J Heart Lung Transplant 2004;23:933-947.[Medline]
6. Hirsch R, Huddleston CB, Mendeloff EN, Sekarski TJ, Canter CE. Infant and donor organ growth after heart transplantation in neonates with hypoplastic left heart syndrome J Heart Lung Transplant 1996;15:1093-1100.[Medline]
7. Glauser TA, Rorke LB, Weinberg PM, Clancy RR. Congenital brain anomalies associated with the hypoplastic left heart syndrome Pediatrics 1990;85:991-1000.[Abstract/Free Full Text]
8. Baum M, Chinnock R, Ashwal S, et al. Growth and neurodevelopmental outcome of infants undergoing heart transplantation J Heart Lung Transplant 1993;12(Suppl):S211-S217.[Medline]
9. Abarbanell G, Mulla N, Chinnock R, Larsen R. Exercise assessment in infants after cardiac transplantation J Heart Lung Transplant 2004;23:1334-1338.[Medline]
10. Ibrahim JE, Sweet SC, Flippin M, et al. Rejection is reduced in thoracic organ recipients when transplanted in the first year of life J Heart Lung Transplant 2002;21:311-318.[Medline]

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				G. Wernovsky The Paradigm Shift Toward Surgical Intervention for Neonates With Hypoplastic Left Heart Syndrome Arch Pediatr Adolesc Med, September 1, 2008; 162(9): 849 - 854. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Sanjiv K. Gandhi Charles B. Huddleston Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gandhi, S. K. Articles by Huddleston, C. B. Search for Related Content PubMed PubMed Citation Articles by Gandhi, S. K. Articles by Huddleston, C. B. Related Collections Transplantation - heart