Trasplante Cardiaco

Registro

The Registry of the International
Society of Heart and Lung Transplantation:
First Official
Pediatric Report-1997

Mark M. Boucek, MD, Richard J. Novick, MD, Leah E. Bennett, MD, Bennie Fmi, BS, Berkeley M. Keck, BS, and Jeffrey D. Hosenpud, MD

The Registry of the International Society of Heart and Lung Transplantation is the first report dedicated to pediatrics. It represents a subset of the entire Registry report ¹.Pediatrics is an established medical specialty, and important issues in pediatrics justify a dedicated investigation and report. Pediatnc thoracic transplantation accounts for approximately 10% of all thoracic transplantations. However, unique aspects such as growth, puberty, immune maturation, decades-long life expectancy, and certain infections make the pediatric population a biologically novel group. Thus the two main issues that drive the pediatric registry report are (1) Indepth analysis of those unique pediatric issues cannot be accommodated by the encompassing registry report and (2) the novelty of pediatrics provides a biologic model that mandates innovation and tailored care for thoracic transplant recipients. New insights may come from scrutiny of the pediatric data that may benefit alí recipients.

From the University of Colorado Health Sciences Center/The Children's Hospital, Denver, Colorado, and coritributing centers.
Reprint requests: International Society for Heart and Lung Transplantation, 14673 Midway Rd., Suite 108, Dallas, TX 75244.
J Reart Lung Transplant 1997;16:1189-206.
Copyright © 1997 by The International Society for Heart and Lung Transplantation.
1053-2498/97/$5.00 + 0 14/1/86183

HEART TRANSPLANTATION

The number of heart transplantations performed during the indicated years is shown as bars in Figure 1, the number of centers reporting data for each indicated year is shown by the solid line (Y₂ axis). The number of centers and transplantations peaked in 1993. There has been a plateau in volume and number of centers since 1990. The indications for heart transplantation was divided into three age ranges, <1 year, 1 to 10 years, and 11 to 17 years and is displayed in Figures 2, 3, and 4, respectively. The youngest recipient group (<1 year) accounts for about one third of all pediatric heart transplant recipients, and the diagnosis of congenital heart disease was the most common indication at 75.5% (Figure 2). Congenital heart disease peaked in 1989 at almost 90% and has decreased to approximately 70% by 1996. Figure 3 shows the indication for recipients aged 4 to 10 years, where a balance between congenital heart disease and myopathy has been present throughout the reporting period. Figure 4 shows the indications for the adolescent age group (11 to 17 years). Myopathy has been the dominant indication for this age group, but congenital heart disease seems to be increasing.

The actuarial survival rate for pediatric heart transplant recipients is shown in Figure 5. By 5 years after transplantation, the early difference in survival, on the basis of age, seems to be lost, and the curves converge. The half-life (50% survival for an pediatric heart transplant recipients) was 11 years. Fully one half of all deaths occur in the first year after transplantation, most within the first 3 months. The slope of the survival curve levels off after the first year, with an annual estimated mortality rate of 2.5% per year in years 1 through 11.

Figure 7 shows the cause of death after transplantation. Early after transplantation, primary graft failure is the predominant cause of death. The group of patients represented under primary graft failure includes those coded as nonspecific graft failure because the time of death after transplantation was early (0 to 30 days) in both groups, and both had a similar distribution. Acute rejection was present in the early group but became more important as a cause of death in the 31-day to 1-year group and remained important beyond 1 year. Cardiac allograft vasculopathy, including patients coded as having chronic rejection, became the predominant cause of death in the group beyond 1 year. Combining the acute rejection group and cardiac allograft vasculopathy group shows that rejection accounts for more than two thirds of ah deaths more than 1 year after transplantation. Infection (bacterial, viral, and fungal) was a minor contributor to death, with a peak in the 31-day to 1-year time frame. The group labeled "Other" was consistent throughout ah time periods and included diagnoses that did not fit the major headings.

Table 1 shows the risk factors identified by multivariant logistic regression for all cases between 1988 to 1996. Decreasing recipient age increased the risk of death after transplantation whereas increasing donor age also increased risk. Cold ischemic times less than the baseline of 3.4 hours seemed to decrease risk of death; however, interestingly, longer ischemic times did not further increase risk.

Patients with an intraaortic balbon pump or a ventilator at the time of transplantation were at increased risk for death. Repeat transplantation also increased risk, which was significant by 1 year. The diagnosis of cardiomyopathy was a positive prognosticator. Female sex became a significant risk factor by 3 years, the time when rejection was the leading cause of death.

The immunosuppressive therapy for pediatric heart transplant recipients is shown in Figure 8. Virtually ah patients receive either cyclosporine or tacrolimus. In contrast to adult recipients, however, only 70% receive prednisone at discharge, which then decreases to 50% by year 2. The majority of patients were not rehospitalized in year 1 (Figure 9), and this percentage increased to greater than 66% rehospitalization free between 1 and 2 years followup. Infection was the leading diagnosis in patients rehospitalized (20%) between years 1 and 2. interestingly, infection was a more common cause of rehospitalization than rejection, but rejection was a much more frequent cause of death. Figure 10 indicates excellent rehabilitation after heart transplantation, with 95% reporting no limitation in activity.

The morbidity rates of pediatric heart transplantation for a subset of patients undergoing transplantation in the United States between April 1994 and December 1996 are presented in Table II. Malignancy, renal dysfunction, diabetes, and hyperlipidemia each occurred in less than 5% of patients at both 1 and 2 years follow-up. The percentage of patients with malignancy was 1.5% at 1 year and 1.3% at 2 years. Hypertension was the most frequent morbidity, occurring in approximately 40% in both years.

Table III sbows the distribution of immunosuppressive agents in patients with hypertension. At year 2, only 50% of patients were receiving prednisone (Figure 8). However, 78% of pediatric patients with hypertension were receiving prednisone, whereas only 42% of patients without hypertension were receiving prednisone. The percentage of patients receiving other irnmunosuppressive medications were roughly equally distributed between patients with and without hypertension.

Overail, this pediatric registry report for heart transplantation presents an optimistic picture. with an expected half-life of 11 years, infrequent rehospitalization, infrequent morbidity (other than hypertension, which seems in part to be related to prednisone), and excellent rehabilitation. Surprisingly, the year when transplantation was performed has not changed the mortality rate, and the early mortality rate remains high. These data should prompt us to find maneuvers to lower early mortality rates and learn more from those children whom we have lost.

LUNG TRANSPLANTATION

Figure 11 shows that pediatric lung transplantation centers and the number of transplantations performed seem to be increasing, but still relatively few procedures are performed at each center. Figure 12 shows the diagnosis leading to transplantation by age. In children younger than 11 years of age, no single diagnosis is most common. After 11 years of age, cystic fibrosis was the diagnosis leading to transplantation in 63% of patients.

The actuarial survival rate after lung transplantation (single, double, bilateral) is shown in Figure 13. There was little difference in survival as a function of age at transplantation. The half-life after lung transplantation was 4.5 years. Most of the deaths occurred in year 1, as was the case in pediatric heart transplantation.

However, in contrast to heart transplantation, there seems to be improvement in early rnortality rates in the most recent era (Figure 14). By 2 years after transplantation, the curves merge. Figure 15 shows the percentage of the leading causes of death. In the postoperative period (0 to 30 days), the cause of death is equally distributed among infection, cardiovascular, and hemorrhage. Primary graft failure is the single most common cause of death but still accounts for less than 50%. Between 31 days and 1 year, Infection plays a relatively larger role, and rejection begins to claim a percentage of patients. After 1 year infection remained a significant cause of death, but rejection and obliterative bronchiolitis became the most common causes of death.

Table IV shows the results of the multivariate logistic regression for death alter long transplantation. The requeriment for life support and patient location in an intensive care unit was strongly associated with early death (odds ratio 8.69; p = 0,0001), which persisted at late follow up. The diagnosis of pulmonary fibrosis and the use of sequential bilateral transplantation were associated with a lower mortality rate. Cold ischemic time increased the odds ratio in a stepwise fashion at 1 year. Several issues related to ABO status of donor or recipient were related to death and rnay be due to the relatively small nurnbers. A recipient with blood group A was at somewhat higher risk, whereas a donor with blood group B increased the odds ratio for patient death. It will be interesting to determine whether these differences persist as the number of patients increase. The match of female donor/female recipient lowered the odds ratio.

Figure 16 shows the immunosuppressive regimen used at the time of discharge, 1 year, and 2 years after transplantation for the group of  lung transplant recipients. As in heart transplant recipients, either cyclosporine or tacrolimus was used in virtually all patients. Similarly, azathioprine was used in the vast majority of the patients, and use of prednisone approached 100%. This was true throughout all time periods.

Figure 17 shows the rehospitalization rate. In the first year, only 45% of patients were rehospitalization free. The most common condition leading hospitalization was an infection. The functional status after lung transplantation is excellent, as were those results from heart transplantation. By 2 year of  fol1ow-up, 96% of patients were believed not have any activity limitations.

Table V shows the morbidity rate after lung transplantation, but the incidence of hypertension less than that noted for heart transplant recipient in spite of the fact that virtually 100% received prednisone. Diabetes was noted in a larger percentage of patients, although, again, the numbers were small. Malignancy was slightly more common in the first year after lung transplantation, and there were no additional cases between year 1 and year 2. Similar to heart transplant recipients, the vast maojority of pediatric patients undergoing lung transplantation have excellent renal function.

HEART-LUNG TRANSPLANTATION

Figure 19 shows the number of heart and lung transplant recipients as a function of year, as shown by the solid bars; the number of centers is indicated by the solid line, in contrast to isolated heart or isolated lung transplantation where the number of patients undergoing transplantation roughly followed the curve for the number of centers. For heart-lung transplantation, the number of centers has been increasing somewhat over the study period, whereas the actual number of transplantations seems to have peaked in about 1989. Thus it seems that each center, on ave rage, is performing less than two heart-lung transplantations per year. The indications for heart-lung transplantation are shown on Figure 20. Again, cystic fibrosis makes its appearance between the ages of 1 to 10 years as a cause for heart-lung transplantation and accounts for about 25% of all patients in the 11 to 17 year age bracket. The most common diagnoses, otherwise, were congenital lung abnormalities and primary pulmonary hypertension. Surprisingly, congenital heart disease accounted for only 8% of the total in the 11 to 17 year age bracket.

Figure 21 shows the actuarial survival rate after heart-lung transplantation. There were no infants in the study population, so there are only two groups, that is, 1 to 10 years and 11 to 17 years. The overall survival rate is shown by the triangles, and the half-life was 2.8 years. The conditional half-life, based on surviving the first year, was 8 years. As in heart or lung transplantation, the greatest number of deaths seems to occur in the first year, but death is accrued at a somewhat higher rate after this first year in the heart-lung transplant recipients, as compared with the isolated heart or lung transplant recipients. The older children do somewhat better than those younger than 10 years of age.

Figure 22 shows the actuarial survival for heartlong transplant recipients as a function of era. Comparing the period between 1988 through 1990 and 1994 through 1996, there does seem to be fewer early deaths. However, if one looks at the interim period between 1991 through 1993, the early mortality rate is similar to the 1994 to 1996 group, but the late mortality rate parallels and approaches the curve for the early period from 1988 through 1990.

Figure 23 shows the cause of death for the heart-lung transplant recipients. In the first 30 days, infection, bleeding, and primary graft failure account for ah deaths. In the first year, infection remains a dominant cause, but there was a fairly large number of patients with either acute or chronic rejection or obliterative bronchiolitis. Beyond 1 year, rejection accounts for the vast majority of deaths in the form of either chronic rejection, obliterative bronchiolitis or cardiac allograft vasculopathy. It is interesting to note the percentage of patients with cardiac allograff vasculopathy as a listed cause of death. The idea of pulmonary protection frorn heart rejection and vasculopathy needs some reconsideration.

Figure 24 shows the immunosuppressive regimens for the heart-lung transplant recipients. As with the lung transplant population, virtually 100% are maintained on prednisone and by year 2, about 30% of the patients had been given tacrolimus as their primary inmunosuppressive agent. Figure 25 shows that the rehospitalization rate for heart-lung transplant recipients was higher than the rate seen in an isolated heart or lung. Only 15% of heart-lung transplant recipients were free from hospitalization at 1 year of  follow-up. This had increased to 33% by 2 years follow-up. Hospitalization for infection was the single most cominon reason for hospital-based care in the first year, but rejection appeared as a leading cause in the second year. In addition to the more frequent need for hospitalized care, Figure 26 shows that the functional status for the heart-lung transplant recipients was less than noted earlier for either of the isolated thoracic organs. At 2 years follow-up, two thirds of the patients were believed to need assistance with activity. The morbidity rate after heart-lung transplantation is comparable to the other thoracic organs (Table VI). Hypertension 15 seen in approximately 50% of patients by 2 years. Diabetes is seen more frequently than in either heart or lung transplant recipients at 16.7%.  Renal function, on average, was quite good in the heart-lung transplant recipients, as in the other organs. The overall picture for the pediatric patient after heart-lung transplantation is less rosy than that for isolated heart or lung. The patients seem to need more frequent hospital care, are less likely to be independent, and have a higher late mortality rate.

CONCLUSIONS

This is the initial report of the Pediatric Transplant Registry. We have attempted to define baseline data for the field with some preliminary forays into the determinants of long-term outcome and quality of life. We anticipate that this activity will continue to look at long-term survival as it relates to pretransplantation conditions and, perhaps, posttransplantation management. We anticipate a more in-depth analysis in the coming years to evaluate the determinants of  late graft loss with, perhaps, more of a focus on the conditional half-life. However, because a large portion of deaths still occur in the early postoperative period, we will try to look further at pretransplantation issues that might help explain the early posttransplantation mortality rate. Some of the difficulty with early death has been in the availability of specific codes to describe patient events, and we will make an effort to modify these codes in th future. Clearly, the contribution of all the contributing centers in the United States and Europe was critical in putting togetber this Pediatric Registry Report and we would like to thank these programs for their timely and accurate submission of data which has made this report possible.

 REFERENCE

1. Hosenpud  JD,  Bennett LE,  Keck BM,   Fiol B,  Novick RJ.   The Registry of the International Society for Heart and Lung Transplantation: fourteenth official report 1997. J Heart Lung Transplant 1997; 16:691-712.