Considerations of waiting time

Infants with hypoplastic left heart syndrome represent a unique subset of infants undergoing cardiac transplantation. At the time of listing, the age of infants with hypoplastic left heart syndrome is the youngest of any group of recipients, with a median of 7 days.⁵ The surgically-palliated patient has the second youngest age at listing, namely six months.⁵ In contrast, patients listed because of other congenital cardiac diseases had a mean age of 5.13 years, and a median age of 1.57 years, while patients listed without congenital cardiac disease were even older.⁵

Suitable infants listed for transplantation are palliated with prostaglandin E-1 to maintain ductal patency while awaiting a suitable donor.⁶ Subsequently, the arterial duct can be stented, and the branches of the pulmonary trunk banded, either surgically⁷ or interventionally to provide stabilization of the pulmonary and systemic blood flows prior to transplantation. The competing outcomes after listing an infant with hypoplastic left heart syndrome are transplantation, death, or surgical palliation. The average times from listing to transplantation are typically shorter for patients with hypoplastic left heart syndrome, at 1.5 months, compared with those who have been surgically palliated, who wait for 2.3 months, and patients with congenital cardiac disease, who wait 2.5 months, or those without congenital heart disease, who wait 2 months.

In the study conducted by the Pediatric Heart Transplant Society, the mean time from listing to transplantation in the patients with hypoplastic left heart syndrome was 1.5 months, and ranged from 1 day to 7.6 months.⁵ The mean time from listing to death pre-transplant was 1.3 months, ranging from 1 day to 4.9 months.⁵ Overall mortality and morbidity while waiting is significant. More children listed with hypoplastic left heart syndrome die while awaiting transplantation compared with other diagnoses listed, with shorter times from listing till death while waiting.⁵ Overall mortality while awaiting transplantation for infants with hypoplastic left heart syndrome, nonetheless, has diminished in the current era. In series collected by the Pediatric Heart Transplant Society since 1993, mortality has dropped from 37% to 21%. In another series, mortality while waiting was 10% after 30 days, and 20% after 90 days.⁸ The cause of death while waiting is cardiac failure in about half, no different than in children who die while waiting for transplantation with other indications. Other causes of death in patients waiting with hypoplastic left heart syndrome include multisystem failure, necrotizing enterocolitis, infection, neurologic causes, arrhythmias, and pulmonary hypertension with right ventricular failure.

While waiting time is dangerous, and providers of care are tempted to reconsider surgical options, the outcomes of crossover from listing to transplant is poor.^{5, 6} In the data collected by the Pediatric Heart Transplant Society, the mean time to first surgical palliation after listing was 30.13 days, the age at first palliation was 43.08 days, and the mortality was 52%. In contrast, mortality of primary Norwood palliation in infants with hypoplastic left heart syndrome is significantly lower, approximately 33%.⁹ Thus, our approach with families who elect primary transplantation for hypoplastic left heart syndrome is to encourage a thoughtful decision regarding management that is not revisited over time.

Outcomes of transplantation in children

In general, outcomes are good, with survival as high as 85%.⁶ For hypoplastic left heart syndrome, select centers have achieved similar survival. In the results reported to the Pediatric Heart Transplant Society,⁵ survival is somewhat lower, with 5 year survival in those with hypoplastic left heart syndrome of 72%, no different from patients transplanted with congenital (72%), or with non-congenital heart disease (78%) (Fig. 1). Approximately half of infants with hypoplastic left heart syndrome survive 5 years from the time of listing, similar to the combined survival from listing in patients with or without other forms of congenital heart disease.⁵ Of note, infants who first underwent surgical palliation prior to listing and transplant have an extremely poor outcome, with survival at 5 years no better than 39%.⁵

Figure 1. Survival following transplantation: by diagnosis (PHTS 1993–1998).

Most deaths occur early after transplantation, usually within the first 3 months. The leading cause of death is early graft failure, defined as cardiac failure within one month after transplantation not attributable to rejection. Rejection and infection are the next most prevalent causes of early death. In surgically palliated patients, causes of death within the first months differ, with pulmonary hypertension, right ventricular failure, and pulmonary hemorrhage being significant causes of death.

Survival rates for initial palliative procedures, such as interventional catheterization or first stage surgical reconstruction, appear comparable to infants with hypoplastic left heart syndrome who are transplanted as a primary procedure (Fig. 2).¹⁰ Comparisons of the post-operative survival of transplantation versus Norwood favor transplantation at all ages up to 7 years¹¹ – while differences in morbidity seem to favor transplantation. In 231 infants with hypoplastic left heart syndrome at four centers of excellence, death was high prior to transplantation, accounting for over half of the 1 year mortality. Transplantation nonetheless, resulted in significantly higher survival at 1 and 5 years when compared with staged surgery. Transplantation had a 1 year survival of 61%, and 5 year survival of 55%, compared with staged surgery, which had a survival at one year of 42%, and at 5 years of 38%.

Figure 2. Comparisons of mortality following staged surgical palliation versus transplantation.

After surgical palliation, families and their physicians can elect either transplantation or completion of staged surgical treatment. Crossing-over, as already discussed, incurs significant risks. Reviewing the database, 23 of the 262 infants with hypoplastic left heart syndrome listed for transplantation underwent surgical palliations.⁵ The mean time to first palliation was 30.1 days, and the mean age at palliation was 43.1 days. Of these patients, nearly half are alive and still waiting, or were considered “too well” and removed from the list and underwent more than one palliative surgery. Of note, patients undergoing palliation prior to listing had a significantly lower survival at 5 years (52%; p = 0.01) compared to the other diagnoses.⁵ As already emphasized, infants who first undergo surgical palliation prior to transplantation have an extremely poor outcome.

Long-term outcomes

Despite the demands of surgery and post-operative management in very young and very sick children, survival has significantly improved in the most recent era, with the most dramatic gains in survival achieved in the first year after transplantation. The strong era effect offers hope that the projected half-life for recipients in the current era will continue to increase and survival for decades will be a reality. There continues to be an ongoing risk of death with time (Fig. 3),² mostly due to the development of coronary arterial disease¹² and, in some cases, rejection. The rate of late graft loss appears to be 2% to 3% per year (Fig. 3), although this rate seems to decrease over time, and may vary with the age at transplantation. Recipients less than one year old at treatment, which includes infants with hypoplastic left heart syndrome, have a lower rate of late graft loss as compared to adolescents.² Many of the late acute rejection episodes that are life-threatening have been related to poor compliance, particularly in adolescents.

Figure 3. Actuarial survival for the period 1982 through 1999. (From: ISHL/UNOS Registry Boucek et al. 2001.)

Unique immunologic variables of donors and recipients during childhood

The ultimate goal of transplantation is donor-specific tolerance. Transplantation during childhood may represent a unique immunologic opportunity because the development of the immune system extends not only into infancy, but continues throughout childhood and adolescence. In support of a favorable immunologic opportunity for transplantation in childhood, survival is higher in many centers for recipients less than 1 year of age, predominantly due to reduced early failure of the transplanted organ.²¹ Younger age at time of transplantation was associated with better survival following induction of polyclonal anti-thymocyte antibodies¹³ and a lower frequency of rejection²² compared with older children. One of the most exciting new observations is that infants apparently lacking significant anti-ABO antibodies can safely undergo transplantation across ABO barriers.²³ If confirmed with larger numbers, this observation provides compelling evidence that graft-specific tolerance, at least to production of B cell-mediated antibodies to blood group antigens, can be achieved in infant recipients.

Favorable induction of tolerance to the transplanted organ in neonatal recipients, many with hypoplastic left heart syndrome, had been anticipated since the cellular, endocrine, and humoral components of the human immune system mature postnatally. For example, the production and the profile of cytokines matures after birth.²⁴ The absolute number of mature T-cells and killer T-cells is lower in the infant^{, 25, 26} naive T-cells are greater than in the adult, and the lymphocyte surface receptor repertoire is age-dependent.²⁷

Further studies will be needed to define age-dependent responses relevant to improving the outcomes of transplantation and immunosuppression. Age-dependent changes in immune function are likely to play a role in survival of the graft. Optimal induction and immunosuppressive regimen may need to be changed in concert with maturation of the immune system. For example, the response to corticosteroids, and possibly other immunosuppressive medications, varies with age.^{28, 29} Infants and children undergoing orthotopic cardiac transplantation typically undergo thymectomy at the time of surgery. Although absence of the thymus does not result in a detectable change in immune function in this population,³⁰ the ability to acquire central tolerance in the absence of a thymus may be compromised and, therefore, could affect long-term survival of the graft. Based on these considerations, strategies to prevent early and late rejection are being evaluated. For example, induction therapy at the¹³ time of transplantation has been evaluated in children using either polyclonal anti-thymocyte antibody alone or in combination with mycophenolate mofetil.³¹

Summary

Future improvements can be expected in cardiac transplantation in children. We continue to advance our understanding of the immune system, and to develop more specific immunosuppressive agents. Ultimately, the future for recipients may be improved by strategies such as induction therapy or donor-derived chimeric destined transfusions, designed to enhance the tolerance of the host to a human leukocyte antigen incompatible graft.³² Improvements in tolerance of the host would allow for reduction or elimination of many, if not all, of the immunosuppressive agents, and for longevity extending well into the adulthood.

Survival, particularly for infants, has improved dramatically in the last decade. The most recent results from the registry of the International Society of Heart and Lung Transplantation/United Network for Organ Sharing show that recipients less than one year old at transplantation, who survive the first year, have greater than a 95% survival to four years (Fig. 1). As late outcomes continue to improve, transplantation will provide a better quality and duration of life for infants with hypoplastic left heart syndrome. It is possible, nonetheless, that some infants will require retransplantation, since the half life of a transplanted heart in children has been about 12 years.² The alternative is conventional surgery with multiple palliative operations, and the need for later transplantation as end-stage cardiac function is reached. Efforts to increase potential donors and donor utilization can be supported by innovative schemes, such as ABO incompatible transplants. Additional efforts are made more urgent when the current data indicate excellent outcomes after transplantation, but a high mortality while waiting for transplantation.

Acknowledgements

Transplantation in children is successful due largely to the dedication of the parents and the programs' coordinators. We acknowledge their invaluable contributions, in particular the efforts of Chris Mashburn. We also acknowledge the editorial assistance of Pat Zurek, and the support of the Steve and Sonia Raymund Endowment, in the preparation of the manuscript.