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The registry of the international society for heart and lung transplantation: sixth official pediatric report—2003
The Registry of the International Society for Heart and Lung Transplantation: Sixth Official Pediatric Report—2003 Mark M. Boucek, MD, Leah B. Edwards, PhD, Berkeley M. Keck, MPH, Elbert P. Trulock, MD, David O. Taylor, MD, Paul J. Mohacsi, MD, and Marshall I. Hertz, MD
T
he international experience with pediatric thoracic organ transplantation continues to increase and the patterns of management and outcome are documented in this Sixth Official Pediatric Report. The most striking change in pediatric thoracic transplant recipients continues to be the improvement in overall survival in recent years. The overall number of pediatric heart–lung and heart and lung recipients has remained stable over the last several years. Thus, the population of patients surviving to 1, 3 or 5 years and beyond continues to increase despite an apparent stable pattern of donors and new recipients. The data for heart and lung recipients support the previously noted trend toward increased conditional survival in infant recipients of thoracic organs. We continue to document evolving trends in induction therapy and maintenance immunosuppression. New Kaplan–Meier curves are presented to demonstrate the incidence of post-transplant morbidity, such as coronary vasculopathy and malignancy. Several additional analyses are presented in this report, displaying the impact of creatinine at the time of transplant and subsequent late survival. A more thorough description of the factors associated and not associated with 1- and 5-year survival are presented. From the International Society for Heart and Lung Transplantation, Addison, Texas. All figures and tables from this report, and a more comprehensive set of Registry slides are available at www.ishlt.org/registries/. Reprint requests: Mark M. Boucek, MD, Department of Pediatric Cardiology, Children’s Hospital, University of Colorado Medical School, 1056 East 19th Avenue, Denver, Colorado 80218. E-mail: [email protected] J Heart Lung Transplant 2003;22:636 – 652. Copyright © 2003 by the International Society for Heart and Lung Transplantation. 1053-2498/03/$–see front matter doi:10.1016/S1053-2498(03)00184-0
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STATISTICAL METHODS Survival rates were calculated using the Kaplan– Meier method1 and compared using the log-rank test. Multivariate analyses were performed using logistic regression analysis. Weights were used to account for incomplete follow-up. Patients with known status (e.g., alive or dead) at the timepoint of interest were assigned a weight of 1; patients with incomplete follow-up were assigned a weight proportional to the length of the interval for which their status was known. For example, in the analysis of survival within 1 year, if a patient were lost to follow-up at 9 months they would be assigned a weight of 0.75 in the multivariate analysis. The results of the multivariate analyses are reported as odds ratios (ORs) with either a corresponding pvalue and/or 95% confidence limits. Factors with an OR significantly greater than 1.0 indicate that the factor is associated with an increased likelihood of the event occurring. Conversely, an OR ⬍1.0 indicates that the event is less likely to occur when that factor is present.
HEART TRANSPLANATION Transplant Volumes and Indications There has been little change in the number of heart transplant procedures or in the breakdown of the ages of the recipients, as shown in Figure 1 The most common age for pediatric heart transplantation is between 0 and 1 year (Figure 2). This first year of life represents the greatest risk from congenital abnormalities of the cardiovascular system that are incompatible with life. There is an increasing number of transplants in the later teenage years as well. Figure 3 depicts donor data from the entire experience from 1982 through 2002; the distribution of donors for pediatric heart recipients follows the
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FIGURE 1 Age distribution of pediatric heart
recipients by year of transplant.
distribution for recipients closely. The majority of donors are within the first 1 or 2 years of life. After this period, the number of donors generally tapers down to the mid-teenage years. Finally, a fairly large number of donors from the adult age brackets have been utilized in pediatric heart transplantation. The proportion of infants requiring transplantation based on diagnosis is shown in Figure 4. For
FIGURE 2 Age distribution of pediatric heart recipients for transplants performed between January 1982 and June 2002.
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FIGURE 4 Diagnosis in pediatric heart transplant recipients (age ⬍1 year).
the total experience, approximately 75% of the infants are transplanted for congenital cardiac anomalies. This number decreased throughout the 1990s and has plateaued at about 60% since about 1999. Approximately 30% of infants have cardiomyopathy as the diagnosis leading to transplantation. For the childhood-age years (1 to 10 years of age) cardiomyopathy accounts for the majority of all heart transplants performed, but a balance has developed between patients with cardiomyopathy and those with congenital heart disease; this balance has been fairly stable over the last 3 years. The number of re-transplants remains small; only 5% of the patients transplanted in their childhood years have the diagnosis of re-transplantation. This is important, because the most common single age for transplant is ⬍1 year, and it is likely that the re-transplant population between the ages of 1 and 10 years received their primary heart transplant during infancy. The adolescent age group (11 to 17 years of age) continues to show a predominance of cardiomyopathic disease leading to transplant (Figure 6). Congenital heart disease is also common, and has accounted for approximately 25% of all adolescent transplants in the last 10 years. As noted in the other age groups, re-transplantation remains relatively uncommon and accounts for only 4% of adolescent heart transplants.
Immunosuppression
FIGURE 3 Age distribution for donors of pediatric heart recipients for transplants performed between January 1982 and June 2002.
The patterns of immunosuppressive agents used for pediatric patients in the recent era are shown in Figures 7 to 11. Figure 7 shows the percent of patients receiving induction immunotherapy. Almost 40% of patients currently receive some type of induction therapy. The most common agents are polyclonal anti-thymocyte preparation, used in about 25% of instances. The monoclonal antibody,
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FIGURE 5 Diagnosis in pediatric heart transplant
recipients (ages 1 to 10 years).
OKT3, was used in about 5% of patients and the interleukin-2 receptor (IL-2R) antagonist antibodies were used in approximately 10%. Figure 8 shows the pattern of induction immunotherapy, broken down by year. Overall, it appears that the use of IL-2R antagonist antibodies has been increasing with perhaps some reduction in the use of OKT3. The use of a polyclonal anti–T-cell antibody has
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FIGURE 8 Induction immunosuppression by year of
transplants in pediatric heart recipients for follow-ups between January 2000 and June 2002.
varied from 20% to approximately 33%, but there is no clear trend. Maintenance immunosuppression medications are shown in Figure 9, which displays the percent of patients who were on a given immunosuppressive agent at any time during the follow-up period between January 2000 and June 2002.
FIGURE 9 Maintenance immunosuppression at any
FIGURE 6 Diagnosis in pediatric heart transplant recipients (ages 11 to 17 years).
FIGURE 7 Induction immunosuppression in pediatric heart recipients for follow-ups between January 2000 and June 2002.
time during the follow-up period in pediatric heart recipients for follow-ups between January 2000 through June 2002.
FIGURE 10 Maintenance immunosuppression at time
of follow-up in pediatric heart recipients for follow-ups between January 2000 through June 2002.
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FIGURE 11 Maintenance immunosuppression drug
combinations at time of follow-up in pediatric heart recipients for follow-ups between January 2000 through June 2002.
Cyclosporine is still the primary T-cell activation inhibitor reported at both Years 1 and 5 and, by adding the columns for cyclosporine and tacrolimus, it appears that virtually all patients are maintained on one of these calcineurin inhibitors. The percent of patients reported to be on rapamycin remains extremely low. The use of mycophenolate mofetil (MMF) is more common in the first year than by the fifth year, and the percent of patients on azathioprine (AZA) is stable. Prednisone use is reported in about 75% of patients in the first year, whereas, by 5 years post-transplant, this decreases to approximately 40%. Figure 10 shows immunosuppression at the 1-year follow-up or 5-year follow-up as reported between January 2000 and June 2002. The data appear similar to those shown in Figure 9, although the percent of patients reported to be on MMF or prednisone at 1 year is lower than the cumulative exposure during the first year. The common combinations of immunosuppressive agents reported during Year 1 or Year 5 post-transplant are shown in Figure 11. In general, the combination of cycloporine or tacrolimus with MMF is less frequent in Year 5 than in Year 1. By 5 years, the percentage of patients with various other combinations or regimens increases to about 25%. The use of prednisone is not displayed in any of these combinations. As shown in Figures 9 and 10, very few patients are on rapamycin, and thus it is has not been included in the combinations. Obviously, many more combinations and permutations of immunosuppressive regimen are possible and are used in clinical practice; as more immunosuppressive agents become available these combinations will become even more complex. We hope to track outcomes as a function of immunosuppression; however, the small pediatric popu-
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FIGURE 12 Actuarial survival for pediatric heart
transplants performed between January 1982 and June 2001.
lation will make it difficult to detect minor differences in outcome.
Outcomes Survival. The actuarial survival for pediatric heart recipients is shown in Figure 12. There is a statistically significant difference in survival curves based on recipient age at the time of transplant, with the infant-age population having a greater early mortality than either of the older age groups. However, by 12 years post-transplant, both the childhood and adolescent survival curves have intersected the infant survival curves, indicating a lower rate of late mortality in the infant age group. In fact, the half-life for the infant age group is not computable, because, by 13 years, it has not penetrated the 50% survival barrier. For children at the ages of 1 and 10 years, the half-life is 12.4 years, based on the entire experience since 1982. For the adolescent age group, the half-life is 11 years. Figure 13 shows the conditional actuarial survival, which traces the subsequent survival for patients who have survived the
FIGURE 13 Actuarial survival, conditional on survival to 1 year, for pediatric heart transplants performed between January 1982 and June 2001.
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FIGURE 14 Actuarial survival by era for pediatric
heart transplants performed between January 1982 and June 2001.
first year after transplantation for the same patient cohort. There is a significant survival advantage for both the infant and childhood age ranges as compared with adolescents. However the lower rate of late mortality seen in both infant and childhood age ranges makes calculating a conditional half-life for these age brackets impossible at this time. The actuarial survival for pediatric heart recipients, broken down by era at transplantation, is shown in Figure 14. As noted in previous reports, survival has increased steadily with each era. The most recent era, from 1998 to 2001, was significantly different from any of the previous eras. The dramatic improvement with era is seen in the calculated half-life for patients transplanted between 1982 and 1987: The expected half-life was 6.6 years in the early 1980s, but for patients transplanted between 1988 and 1992 the half-life increased to 11.7 years. In the most recent era survival has continued to increase, but the half-life is not yet computable. Most of the improved survival appears to be evident within the first few months after transplantation, and probably reflects changes in techniques at the time of transplantation and in early immunosuppressive therapy. It is too early to tell whether there is a difference in late survival by era, but the slopes of the curves appear to be roughly parallel. An attempt to look at late survival in the most recent era is shown in Figure 15, in which conditional actuarial survival was broken down by age at the time of transplant. Thus, patients who survived to 1 year are subsequently followed to evaluate late survival, eliminating the impact of early post-transplant mortality. As can be seen in Figure 15 the curves are nearly identical. The infant and childhood age ranges tend to have somewhat better conditional survival until 4 years after transplantation, but these differences are not significant.
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FIGURE 15 Actuarial survival for recent era,
conditional on survival to 1 year, for pediatric heart transplants performed between January 1997 and June 2001.
A possible interplay between immunosuppressive regime and conditional actuarial survival for patients transplanted between April 1994 and June 2001 is shown in Figure 16. Because only about half of pediatric heart transplant recipients receive prednisone through the first year after transplantation, it is possible to look at survival as a function of this immunosuppressive agent. Figure 16 shows a significantly different survival curve based on long-term use of prednisone: Those patients who were either never given prednisone as part of maintenance immunosuppression and those initially started on prednisone and then discontinued before the first year have similar survival curves beyond the first year. However, the sub-group of patients receiving prednisone at the time of transplant and through the first year have lower subsequent survival. It is not clear whether this is a direct effect of the immunosuppressive agent, or a marker for other risk factors or management techniques. An analysis of survival was also performed for pediatric heart patients with a history of rejection during the first year after transplantation. Figure 17
FIGURE 16 Actuarial survival based on prednisone use for pediatric heart transplants performed between April 1994 and June 2001.
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FIGURE 17 Actuarial survival based on rejection
within Year 1 for pediatric heart transplants performed between April 1994 and June 2001.
shows the conditional actuarial survival beyond the first year after transplantation for patients who were free from rejection during the first year after transplantation compared to those with a history of rejection within the first year. There is a statistically significant difference in late survival based on history of rejection within the first year. A greater percentage of patients were reported to have rejection during the first year, but the population of patients in both groups is fairly large, making an analysis in survival difference robust; however, the actual difference in survival was ⬍10% by 8 years post-transplant.
Risk Factors for Mortality The diagnosis leading to transplantation continues to be a highly significant risk factor for mortality in the first year (Table I). The data from the current report mirrors the data in previous pediatric Registry reports, showing that congenital heart disease and diagnoses other than cardiomyopathy are associated with greater risks for 1-year mortality. The pre-transplant status of the patient, including the environment, are also risk factors, as reflected by the history of hospitalization and need for mechanical ventilation, which increases the risk for mortality. Continuous factors related to 1-year mortality in-
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FIGURE 18 Impact of recipient age on the odds of
mortality within 1 year for pediatric heart transplants performed between January 1995 and June 2001 (n ⫽ 2,055).
clude recipient age, bilirubin, serum creatinine and decreasing donor weight. The issue of donor weight is not related to the specific ratio between recipient and donor weight, but rather the absolute weight of the donor over the spectrum of pediatric recipients. The inverse relationship of mortality with absolute donor weight probably reflects the increased risk associated with younger age of the recipient and congenital diagnosis leading to transplant in the recipient. The relationship between recipient age and risk of 1-year mortality is shown in Figure 18. It is of interest to note that a similar U-shaped curve is seen in adult recipients as well, but there is no clear explanation for this finding. Figure 19 shows the relationship between serum creatinine at the time of transplantation and odds of 1-year mortality. The number of patients with high creatinine values is small and thus the p-value is of borderline statistical significance, but the relationship appears convincing. Creatinine potentially could serve as a quantifiable marker for risk at the time of transplantation. Among factors that were not significant in multivariate modeling for risk of 1-year mortality were the need for intravenous inotropes, prostaglandin infusion and extracorporeal membrane oxygenation
TABLE I Risk factors for mortality within 1 year for pediatric heart transplants performed between January 1995 and June 2001 (N ⫽ 2,055) Risk factor
Odds ratio
p-value
95% confidence interval
Congenital heart disease Other diagnosis (excluding cardiomyopathy and re-transplant) Hospitalized (including ICU) Ventilator
2.00 1.97 1.56 1.76
⬍0.0001 0.04 0.004 0.0008
1.53–2.62 1.02–3.82 1.16–2.10 1.26–2.44
ICU, intensive care unit.
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FIGURE 19 Impact of recipient creatinine on the odds
of mortality within 1 year for pediatric heart transplants performed between January 1995 and June 2001 (n ⫽ 2,055).
(ECMO) as well as a history of prior sternotomy or recent infection. Some of these factors were previously identified as risk factors, but in this most recent analysis the relationship was no longer observed. Donor factors not associated with 1-year mortality in the recipient include history of clinical infection, age and cause of death. Interestingly, donor/recipient combined factors not related to 1-year mortality included the donor/recipient weight ratio, cytomegalovirus (CMV) mismatch, ischemia
FIGURE 20 Impact of recipient creatinine on the odds of mortality within 5 years for pediatric heart transplants performed between January 1995 and June 1997 (n ⫽ 630).
time, HLA mismatches, panel-reactive antibody (PRA) and transplant center volume. The risk factors for 5-year mortality continue to include the need for a ventilator at the time of transplant, recipient age and serum creatinine. Prior sternotomy appears again as a risk factor for 5-year mortality, but may be influenced by the era during which the cohort was transplanted. The relationship between recipient serum creatinine and the odds of 5-year mortality is shown in Figure 17. As shown for 1-year mortality, serum creatinine has a direct relationship to the odds of 5-year mortality. The factors evaluated that were not related significantly to 5-year mortality for pediatric heart transplant recipients include the need for intravenous inotropic agents, need for ECMO, recent diagnosis of infection, and the need for hospitalization at the time of transplantation. Donor factors not significantly related to 5-year mortality include history of infection in the donor, gender, weight, age and cause of death. Transplant factors not significantly related to 5-year mortality include the donor/recipient weight ratio, CMV mismatch, ischemia time, HLA mismatch, PRA and transplant center volume. Because most of the mortality for pediatric recipients occurs in the early post-transplant period, the early mortality may overwhelm factors that could be related to 5-year mortality. To reduce this effect, an analysis was performed conditional on the survival of the patient to 1 year after transplantation. In this multivariate analysis, factors associated with 5-year mortality include re-transplantation, the need for intravenous inotropic medications at the time of transplantation, and treatment for rejection within the first posttransplant year (Table II). Interestingly, the need for prostaglandin infusion was also related to 5-year mortality. Prostaglandin infusion would be required in the sub-set of infants with ductal-dependent circulation. Often, these patients have hypoplastic left heart syndrome; previous Registry reports have shown patients with this condition to have a high
TABLE II Risk factors for mortality within 5 years, conditional on survival to 1 year, for pediatric heart transplants performed between January 1995 and June 1997 (N ⫽ 630) Risk factor
Odds ratio
p-value
95% confidence interval
Re-transplant Intravenous inotropes PGE Hospitalized for rejection or treated with anti-rejection medications between discharge and 1 year
4.68 2.06 4.05 2.39
0.003 0.01 0.03 0.003
1.68–3.01 1.19–3.56 1.15–14.25 1.36–4.19
PGE, prostaglandin estradiol.
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TABLE III Cause of death for pediatric heart transplant recipients for deaths between January 1992 and June 2002 Cause of death Coronary vasculopathy Acute rejection Lymphoma Malignancy, other CMV Infection, non-CMV Primary failure Graft failure Technical Other Multiple-organ failure Renal failure Pulmonary Cerebrovascular
0 to 30 days (N ⴝ 276)
31 days to 1 year (N ⴝ 231)
>1 year to 3 years (N ⴝ 147)
>3 years to 5 years (N ⴝ 93)
>5 years (N ⴝ 156)
2 (0.7%) 25 (9.1%)
21 (9.1%) 66 (28.6%) 5 (2.2%) 4 (1.7%) 5 (2.2%) 37 (16.0%) 12 (5.2%) 28 (12.1%) 3 (1.3%) 7 (3.0%) 23 (10.0%) 1 (0.4%) 12 (5.2%) 7 (3.0%)
32 (21.8%) 39 (26.5%) 8 (5.4%) 1 (0.7%)
35 (37.6%) 15 (16.1%) 2 (2.2%) 1 (1.1%)
54 (34.6%) 20 (12.8%) 14 (9.0%) 6 (3.8%)
11 (7.5%) 5 (3.4%) 25 (17.0%) 2 (1.4%) 8 (5.4%) 3 (2.0%)
5 (5.4%) 6 (6.5%) 17 (18.3%) 1 (1.1%) 4 (4.3%) 1 (1.1%)
5 (3.2%) 10 (6.4%) 30 (19.2%) 2 (1.3%) 8 (5.1%) 1 (0.6%)
7 (4.8%) 6 (4.1%)
5 (5.4%) 1 (1.1%)
4 (2.6%) 2 (1.3%)
1 (0.4%) 38 (13.8%) 44 (15.9%) 76 (27.5%) 17 (6.2%) 7 (2.5%) 24 (8.7%) 1 (0.4%) 22 (8.0%) 19 (6.9%)
CMV, cytomegalovirus.
risk of mortality, and survivors to have a possibly enduring detrimental legacy, a hypotheses that deserves further study.
Cause of Death Table III displays the causes of death for recipients of transplants between January 1992 and June 2002. Early graft failure is the leading cause of death and accounts for about 32% of deaths during the first 30 days. During the first year, acute rejection becomes the leading single cause accounting for almost 30% of deaths. It is likely that a percentage of patients listed as graft failure may also have had acute rejection. Between 1 and 3 years after transplantation, acute rejection continues to be the leading cause of death, occurring in approximately 25% of the patients, but coronary vasculopathy now accounts for about 20%, and there is a persistent incidence of graft failure that could represent either graft rejection or coronary vasculopathy. Beyond 3 years, acute rejection remains an important cause of death, but coronary artery vasculopathy is clearly the predominant cause of death, accounting for approximately 33% of all late deaths. Interestingly, graft failure continues to be represented in as many as 20% of patients at ⬎5 years post-transplant. This group of patients could represent biopsy-negative late acute rejection or undiagnosed coronary artery vasculopathy. Because of the multi-institutional nature of the Registry data, we are unable to tease out the causes of graft failure in this relatively large group of patients.
Specific Complications Table IV shows the cumulative prevalence of several morbid events in survivors during the first posttransplant year. As has been reported in previous Pediatric Registry reports, hypertension is the most common event and is found at some point during the first year in 44% of patients. Renal dysfunction remains infrequent, as do hyperlipidemia, diabetes and coronary vasculopathy (Table V). Cumulatively, hypertension is seen in 60% of patients within 5 years, but renal dysfunction remains relatively infrequent, and clearly significant levels of renal dysfunction are uncommon. Hyperlipidemia has a cumulative incidence of 17%, but diabetes remains infrequent, and in pediatric recipients coronary vas-
TABLE IV Post-transplant morbidity in pediatric heart transplant recipients within 1 year, based on follow-ups between April 1994 and June 2002: cumulative prevalence in survivors Outcome Hypertension Renal dysfunction Abnormal creatinine ⬍2.5 mg/dl Creatinine ⬎2.5 mg/dl Long-term dialysis Renal transplant Hyperlipidemia Diabetes Coronary vasculopathy
Within 1 year 44.2% (N ⫽ 1,507) 5.1% (N ⫽ 1,516) 3.2% 1.4% 0.5% 0.0% 8.6% (N ⫽ 1,578) 3.2% (N ⫽ 1,509) 2.5% (N ⫽ 1,363)
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TABLE V Post-transplant morbidity in pediatric heart transplant recipients within 5 years, based on follow-ups between April 1994 and June 2002: cumulative prevalence in survivors Outcome Hypertension Renal dysfunction Abnormal creatinine ⬍2.5 mg/dl Creatinine ⬎2.5 mg/dl Long-term dialysis Renal transplant Hyperlipidemia Diabetes Coronary vasculopathy
Within 5 years 60.0% (N ⫽ 365) 7.5% (N ⫽ 389) 5.9% 0.8% 0.8% 0.0% 17.1% (N ⫽ 398) 4.9% (N ⫽ 366) 11.4% (N ⫽ 228)
culopathy is reported in only 11% of survivors up to 5 years after transplantation. Actuarial freedom from coronary artery vasculopathy in pediatric heart recipients is shown in Figure 21. There is a steady decrease in freedom from coronary vasculopathy through at least 7 years post-transplant. However, over 75% of pediatric recipients remain free from vasculopathy at 7 years. Figure 22 shows the actuarial freedom from coronary vasculopathy as a function of age of recipient. Adolescent recipients appear to be at greater risk for vasculopathy and infants at the lowest risk for vasculopathy. Figure 23 displays survival after a diagnosis of coronary artery vasculopathy, according to recipient age. In contrast to Figure 22, infants appear to be at greatest risk for death after a diagnosis of coronary vasculopathy, with adolescent patients seemingly at lowest risk. However, by 2 years after diagnosis of vasculopathy, survival approaches 60% for all pediatric recipients. It is not clear whether these observations reflect differences in biology or differences in diagnostic technique. The infant age group would be the most
FIGURE 21 Freedom from CAV in pediatric heart
recipients for follow-ups between April 1994 and June 2002.
FIGURE 22 Freedom from CAV, stratified by age group, in pediatric heart recipients for follow-ups between April 1994 and June 2002.
difficult to diagnose in the early stages of vasculopathy, because angiography is the primary diagnostic test and the sensitivity of angiography in infants may be lower than in older recipients. Actuarial freedom from severe renal dysfunction, defined as creatinine ⬎2.5 mg/dl or the need for dialysis or renal transplant, is shown in Figure 24). Again, a steady decrease in freedom from severe
FIGURE 23 Survival after report of CAV, stratified by age group, in pediatric heart recipients for follow-ups between April 1994 and June 2002.
FIGURE 24 Freedom from severe renal dysfunction in pediatric heart recipients for follow-ups between April 1994 and June 2002.
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FIGURE 27 Age distribution of pediatric lung FIGURE 25 Freedom from malignancy in pediatric
heart recipients for follow-ups between April 1994 and June 2002.
renal dysfunction is evident through 7 years posttransplant, reflecting the known nephrotoxic effects of calcineurin inhibitors. The slope of the freedom from renal dysfunction curve is relatively flat, such that 90% of pediatric heart recipients are free of severe renal dysfunction at 7 years post-transplant. Figure 25 shows freedom from malignancy for pediatric heart recipients. It is evident from this figure that lymphoproliferative malignancies account for virtually all pediatric malignancies. A steady decrease in freedom from malignancy with time is noted for at least 7 years after transplantation. Fortunately, like renal dysfunction, the slope is relatively flat, and by 7 years 90% are free from malignancy. The functional status of pediatric heart recipients continues to be excellent, as shown in Figure 26. At all time periods after transplantation, ⬎95% of the surviving patients are reported to have no activity limitations. In summary, the pediatric heart transplantation data continue to document improving survival, primarily through a reduction in early mortality. Morbidity is most commonly represented in the form of
FIGURE 26 Functional status in pediatric heart
recipients for follow-ups between April 1994 and June 2002.
recipients by year of transplant.
hypertension, which has been shown in previous Registry reports to be related at least in part to prednisone use. Late survival is adversely influenced by acute rejection and the development of coronary vasculopathy. Repeat transplant procedures also increase the risk for late mortality and the development of coronary vasculopathy. Of the risk factors for early mortality, diagnosis, age, ventilator requirement, serum creatinine, and hospitalization at the time of transplant are significant contributors. Based on these observations we can begin to envision an unfortunate model patient at risk for early and late mortality. Perhaps the pediatric heart transplant community will be able to use this information to fashion strategies to reduce the risk of mortality and optimize the freedom from morbidity after pediatric heart transplantation.
LUNG TRANSPLANTATION Transplant Volumes and Indications The number of pediatric lung transplant procedures has decreased slightly since the late 1990s. As shown in Figure 27, the majority of recipients are still in the adolescent age range with most of the decline in number occurring in young children and infants. The age distribution of pediatric lung transplant recipients between 1988 and 2002 is shown in Figure 28. Most recipients were between 11 and 17 years of age, with the nadir between 2 and 7 years of age. Among younger aged pediatric recipients, the first year of life is the most likely time for lung transplantation. The indications for pediatric lung transplant recipients ⬍10 years of age are shown in Table VI. In the infant age group, congenital heart disease was the most common indication for lung transplantation, but thereafter the most common indication was cystic fibrosis. Primary pulmonary hypertension and congenital heart disease are the two other most common indications for younger children. Figure 29
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FIGURE 29 Diagnosis in 11- to 17-year-old pediatric
FIGURE 28 Age distribution of pediatric lung
lung recipients.
recipients for transplants performed between January 1986 and June 2002.
preparations. Figure 31 shows the maintenance immunosuppression administered to pediatric lung recipients at 1- and 5-year follow-up. The 1-year cohort shows a preponderance of tacrolimus as the primary calcineurin inhibitor, but for the 5-year cohort cyclosporine was most frequent. Rapamycin use remained low in both cohorts. There is an even breakdown between the use of MMF and AZA, and virtually all patients were on prednisone at both 1 and 5 years.
shows the diagnoses leading to pediatric lung transplantation for adolescent recipients. Cystic fibrosis has steadily increased as an indication leading to transplant and now accounts for about 67% of all adolescent lung recipients. The percentage of patients with primary pulmonary hypertension decreased during the 1990s, and overall accounts for approximately 10% of adolescent recipients.
Immunosuppression
Outcomes
Induction immunotherapy is used in a majority of pediatric lung recipients. Figure 30 shows the percent of patients receiving any induction therapy and a breakdown between polyclonal anti–T-cell preparations and IL-2R antagonist antibody preparations. The relative proportion of these agents has remained stable in the period between January 2000 through June 2002, with about 30% receiving IL-2R antagonists and roughly 20% polyclonal anti–T-cell
Survival. Figure 32 shows the actuarial survival by era for pediatric lung transplant recipients. Comparing the era of 1998 to 1992 to the most recent era of 1998 to 2001, there was no significant difference in actuarial survival. The half-life in the former era was 2.6 years, and in the latter was 3.1 years. The half-life for survival conditional upon surviving the first year was 8.2 years in the former era and 5.7
TABLE VI Indications for transplant in pediatric lung transplants performed between January 1991 and June 2002 Age < 1 year Indication Cystic fibrosis Primary pulmonary hypertension Congenital heart disease Idiopathic pulmonary fibrosis Pulmonary vascular disease Re-transplant: not obliterative bronchiolitis Re-transplant: obliterative bronchiolitis Obliterative bronchiolitis (not re-transplant) Bronchiectasis COPD/emphysema Other COPD, chronic obstructive pulmonary disease.
Age 1–10 years
N
%
7 20
17.1% 48.8%
5 3
12.2% 7.3%
6
14.6%
N
%
56 24 19 12 6 8 10 6 2 2 19
34.1% 14.6% 11.6% 7.3% 3.7% 4.9% 6.1% 3.7% 1.2% 1.2% 11.6%
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FIGURE 30 Induction immunosuppression in pediatric
lung recipients for follow-ups between January 2000 and June 2002.
years in the latter era. By 10 years after transplantation, the overall survival was ⬍40%. Figure 33 compares survival by age group for the period between January 1990 and June 2001, showing no significant difference. Figure 34 shows conditional actuarial survival according to age group; in this analysis, late survival depends on surviving to the
FIGURE 31 Maintenance immunosuppression at time of follow-up in pediatric lung recipients for follow-ups between January 2000 and June 2002.
FIGURE 32 Actuarial survival by era for pediatric lung transplants performed between January 1988 and June 2001.
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FIGURE 33 Actuarial survival by age group for
pediatric lung transplants performed between January 1990 and June 2001.
first year, and then subsequent analysis is performed. These survival curves are not significantly different, but there appears to be a trend toward increased survival in infants. This observation, if it strengthens with further analysis, would be similar to the observation seen in pediatric heart transplant recipients. Survival after pediatric lung transplantation may be influenced by the type of procedure, as shown in Figure 35. Actuarial survival was significantly better in patients receiving bilateral or double-lung transplants as compared with single-lung transplants. The inset demonstrates that the vast majority of pediatric recipients receive either bilateral or double-lung procedures. The diagnosis leading to transplantation appears to have a large effect on post-transplant survival, depending on the type of procedure performed. Figure 36 shows the actuarial survival for single- vs double-lung transplantation for patients with primary pulmonary hypertension. There is a highly significant difference in survival, but the number of patients is relatively small. Patients with primary pulmonary hyperten-
FIGURE 34 Actuarial survival by age group,
conditional on survival to 1 year, for pediatric lung transplants performed between January 1990 and June 2001.
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FIGURE 35 Actuarial survival by procedure type for
pediatric lung transplants performed between January 1990 and June 2001.
sion who received double-lung transplants had an actuarial survival at 10 years of approximately 50%, in contrast to patients who received a single lung and had an actuarial 10-year survival of approximately 10%.
Cause of Death Table VII displays the cause of death for pediatric
FIGURE 36 Actuarial survival by procedure type in
patients with primary pulmonary hypertension for pediatric lung transplants performed between January 1990 and June 2001.
lung recipients according to time since transplantation. In the 0- to 30-day post-transplant timeframe, graft failure is the leading cause of death, occurring in almost 50% of patients. In the period between 30 days and 1 year after transplantation, infections other than CMV account for 41% of deaths, easily the leading cause of death. Between 1 and 3 years post-transplant, bronchiolitis obliterans becomes the most common cause in 37% of patients, followed by infection other than CMV in 21%. Beyond 3 years, obliterative bronchiolitis remains the single most common cause of death, occurring in about 45% of patients. The trend toward increased death due to obliterative bronchiolitis mirrors the trend toward increasing cause of death in heart recipients due to coronary artery vasculopathy. Both of these phenomena likely represent rejection-related problems in the respective organs.
Specific Complications Morbidity is common after pediatric lung transplantation. Table VIII shows the cumulative incidence of a number of adverse outcomes in survivors between 1994 and June 2002. By 1 year post-transplant, 37% of patients are reported to have hypertension, increasing to 74% by 5 years. As in heart transplantation, renal dysfunction is uncommon by 1 year and significant renal dysfunction is infrequent. By 5 years, the percentage increases to 24%, and ⬎10% of survivors have creatinine ⬎2.5 mg/dl, long-term dialysis or renal transplantation. Hyperlipidemia is uncommon in the lung transplant population at both 1 and 5 years. Diabetes occurs in 20% of patients by 1 year and 31% of patients by 5 years. Previous analyses of Pediatric Registry data show a strong correlation between a diagnosis of cystic fibrosis and later development of diabetes after transplantation.
TABLE VII Cause of death for pediatric lung transplant recipients for deaths between January 1992 and June 2002 Cause of death Bronchiolitis Acute rejection Lymphoma CMV Infection, non-CMV Graft failure Cardiovascular Technical Other
0 to 30 Days (N ⴝ 45)
31 days to 1 Year (N ⴝ 75)
>1 year to 3 years (N ⴝ 81)
>3 years to 5 years (N ⴝ 35)
>5 years (N ⴝ 11)
30 (37.0%)
16 (45.7%) 1 (2.9%) 1 (2.9%)
5 (45.5%) 2 (18.2%)
6 (13.3%) 20 (44.4%) 6 (13.3%) 6 (13.3%) 7 (15.6%)
5 (6.7%) 3 (4.0%) 3 (4.0%) 5 (6.7%) 31 (41.3%) 14 (18.7%) 2 (2.7%) 1 (1.3%) 11 (14.7%)
17 (21.0%) 16 (19.8%) 2 (2.5%)
8 (22.9%) 3 (8.6%)
1 (9.1%) 2 (18.2%)
12 (14.8%)
6 (17.1%)
1 (9.1%)
4 (4.9%)
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TABLE VIII Post-transplant morbidity in pediatric lung transplant recipients within 1 year and within 5 years, based on follow-ups between April 1994 and June 2002: cumulative prevalence in survivors Outcome Hypertension Renal dysfunction Abnormal creatinine ⬍2.5 mg/dl Creatinine ⬎2.5 mg/dl Long-term dialysis Renal transplant Hyperlipidemia Diabetes Bronchiolitis obliterans
Within 1 year
Within 5 years
37.7% (N ⫽ 313) 7.6% (N ⫽ 315) 5.1% 1.6% 0.6% 0.3% 0.9% (N ⫽ 326) 21.0% (N ⫽ 314) 14.7% (N ⫽ 286)
73.7% (N ⫽ 57) 24.1% (N ⫽ 58) 12.1% 6.9% 3.4% 1.7% 1.7% (N ⫽ 59) 31.0% (N ⫽ 58) 20.5% (N ⫽ 39)
Bronchiolitis obliterans is a leading cause of late mortality after pediatric lung transplantation, and in survivors the cumulative incidence is 14.7% at 1 year, which increases to 20% by 5 years. Figure 37 displays the actuarial freedom from bronchiolitis obliterans for pediatric recipients; by 4 years, half of the pediatric recipients have experienced this morbid event. Figure 38 shows the actuarial freedom from significant renal dysfunction, defined as creatinine ⬎2.5 mg/dl, dialysis or renal transplant. More pediatric lung recipients are affected by significant renal dysfunction than pediatric heart recipients. This difference is probably a reflection of the increased immunosuppression used for lung transplant recipients as well as concomitant medications used to treat frequent infectious complications after lung transplantation. Figure 39 displays the freedom from malignancy in pediatric lung recipients. As is the case for heart recipients, lymphoproliferative abnormalities account for the vast majority of malignancies. By 6 years post-transplant, approximately 85% remain free from malignancy, slightly lower than that seen after heart transplantation.
Functional Status
FIGURE 37 Freedom from bronchiolitis obliterans in
FIGURE 39 Freedom from malignancy in pediatric
pediatric lung recipients for follow-ups between April 1994 and June 2002.
Re-hospitalization after lung transplantation is more common than after heart transplantation. However, with time, hospitalization becomes less frequent; most hospitalizations are either for infection alone or in combination with rejection. Figure 40 shows the breakdown in re-hospitalization by time post-transplant and by reason for hospitaliza-
FIGURE 38 Freedom from severe renal dysfunction in pediatric lung recipients for follow-ups between April 1994 and June 2002.
lung recipients for follow-ups between April 1994 and June 2002.
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FIGURE 40 Re-hospitalization post-transplant in
pediatric lung recipients for follow-ups between April 1994 and June 2002.
tion. Between 4 and 5 years, 60% of patients do not require hospitalization for management. Figure 41 displays the functional status of pediatric lung recipients as a function of time since transplantation. Greater than 80% of surviving patients are reported to have no activity limitations through 5 years post-transplant. Again, this is slightly lower than that seen after heart transplantation.
HEART AND LUNG TRANSPLANTATION Transplant Volumes and Indications The volume of pediatric heart–lung transplantation continued to decrease through 2001. Figure 42 shows the number of heart–lung transplant procedures performed by calendar year; the data are further sub-divided by age of the recipient. It can be seen that the number of infant and child recipients has decreased to negligible numbers, and even the number of adolescent recipients has decreased over time. The overall number of procedures performed worldwide in 2001 was approximately 10. Figure 43 shows the number of centers reporting pediatric heart–lung transplants, which has also fallen to approximately 10, indicating that, on average, only 1
FIGURE 41 Functional status in pediatric lung
recipients for follow-ups between April 1994 and June 2002.
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FIGURE 42 Age distribution of pediatric heart–lung recipients by year of transplant.
procedure is performed per center in a given year. Although the Registry will continue to monitor pediatric heart–lung transplant recipients, it is becoming a clinically insignificant activity. Figure 44 shows the number of pediatric heart–lung transplant recipients, broken down by recipient age. Based on the experience in the last 20 years it is clear that the majority of patients are in the adolescent age range. Figure 45 shows the diagnoses leading to pediatric heart–lung transplantation in adolescents; congenital heart disease and cystic fibrosis were the most com-
FIGURE 43 Number of centers reporting pediatric heart–lung transplants.
FIGURE 44 Age distribution of pediatric heart–lung
recipients for transplants performed between January 1982 and June 2002.
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FIGURE 45 Diagnosis in 11- to 17-year-old pediatric heart–lung transplant recipients.
mon diagnoses leading to pediatric heart–lung transplantation. A trend analysis from 1986 to 2001 is shown at the bottom of Figure 45 for the 3 most common indications leading to transplant; congenital heart disease has remained relatively stable, whereas there were large fluctuations in primary pulmonary hypertension and cystic fibrosis. These fluctuations are primarily due to the small number of recipients, and overall there has not been a dramatic change in the relative percentages of these 3 diagnoses.
Survival Survival after pediatric heart–lung transplantation is shown in Figure 46. There was no significant difference in survival among recipients between 1 and 10 years of age vs the adolescent age range of 11 to 17 years. The calculated half-life for the 1- to 10-yearold age range is 2.0 years, and in the 11- to 17-yearold age range it is 3.3 years. By 10 years after transplantation, the overall survival is approximately 20%. In Figure 47, an era analysis is shown, comparing actuarial survival of pediatric heart–lung transplant recipients vs the era of transplantation. Unlike heart transplant recipients, there is no era
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FIGURE 47 Actuarial survival by era for pediatric
heart–lung transplants performed between January 1982 and June 2001.
effect for heart–lung recipients (Figure 47). In fact, the calculated half-life for the most recent era between 1998 and 2001 is 2 years, which is the lowest for any of the eras evaluated. The conditional half-life for the most recent era is only 3.3 years, which is also the lowest for any of the eras evaluated. This failure to improve survival with time may reflect the diminishing experience available, with most institutions now doing no more than 1 procedure in a given year. These data are difficult to interpret because the numbers are so small; however, the survival curve suggests that a careful re-evaluation of pediatric heart–lung transplantation may be in order. Table IX shows the causes of death after pediatric heart–lung transplantation. As demonstrated in previous years, these data are comparable to those seen after lung transplantation. Graft failure explains 50% of the mortality within the first 30 days, and at ⬎1 year bronchiolitis obliterans accounts for approximately 50% of mortality. Because the number of pediatric heart–lung transplant procedures has become so small and the mortality remains high, an analysis of morbidity was not performed.
CONCLUSIONS
FIGURE 46 Actuarial survival for pediatric heart–lung transplants performed between January 1982 and June 2002.
The number of pediatric heart and lung transplant procedures has remained relatively stable in comparison to recent years. The outcomes for heart transplantation have improved steadily, primarily through a reduction in early mortality. A more thorough analysis of the associated risk factors for early and late mortality and a more thorough analysis of the risk of coronary vasculopathy have been included in this report, as compared with previous years. Coronary vasculopathy is a major cause of late graft failure, and a more thorough understand-
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TABLE IX Cause of death for pediatric heart–lung transplant recipients for deaths between January 1992 and June 2002 Cause of death Bronchiolitis Acute rejection Infection, other Graft failure Technical Other
0 to 30 days (N ⴝ 20)
31 days to 1 year (N ⴝ 24)
>1 year to 3 years (N ⴝ 25)
>3 years to 5 years (N ⴝ 16)
>5 years (N ⴝ 16)
13 (52.0%)
8 (50.0%)
4 (25.0%)
5 (25.0%) 10 (50.0%) 3 (15.0%) 2 (10.0%)
1 (4.2%) 1 (4.2%) 9 (37.5%) 5 (20.8%) 1 (4.2%) 7 (29.2%)
5 (20.0%) 5 (20.0%)
1 (6.3%) 5 (31.3%)
5 (31.3%) 5 (31.3%)
2 (8.0%)
2 (12.5%)
2 (12.5%)
ing and management of this condition will be necessary if we are to see reductions in late mortality similar to those seen with early mortality. Infant recipients seem to be at lower risk for late graft vasculopathy in heart recipients and bronchiolitis obliterans in lung recipients. Pediatric heart–lung transplantation continues to decrease in frequency
and survival rates appear to be decreasing as well. Thus, the ongoing role of this procedure in the management of irreversible pediatric cardiopulmonary disease seems uncertain. The authors wish to thank Dawn Schmeck and Shari Borcherding for assistance in preparing the manuscript.
T
he international experience with pediatric thoracic organ transplantation continues to increase and the patterns of management and outcome are documented in this Sixth Official Pediatric Report. The most striking change in pediatric thoracic transplant recipients continues to be the improvement in overall survival in recent years. The overall number of pediatric heart–lung and heart and lung recipients has remained stable over the last several years. Thus, the population of patients surviving to 1, 3 or 5 years and beyond continues to increase despite an apparent stable pattern of donors and new recipients. The data for heart and lung recipients support the previously noted trend toward increased conditional survival in infant recipients of thoracic organs. We continue to document evolving trends in induction therapy and maintenance immunosuppression. New Kaplan–Meier curves are presented to demonstrate the incidence of post-transplant morbidity, such as coronary vasculopathy and malignancy. Several additional analyses are presented in this report, displaying the impact of creatinine at the time of transplant and subsequent late survival. A more thorough description of the factors associated and not associated with 1- and 5-year survival are presented. From the International Society for Heart and Lung Transplantation, Addison, Texas. All figures and tables from this report, and a more comprehensive set of Registry slides are available at www.ishlt.org/registries/. Reprint requests: Mark M. Boucek, MD, Department of Pediatric Cardiology, Children’s Hospital, University of Colorado Medical School, 1056 East 19th Avenue, Denver, Colorado 80218. E-mail: [email protected] J Heart Lung Transplant 2003;22:636 – 652. Copyright © 2003 by the International Society for Heart and Lung Transplantation. 1053-2498/03/$–see front matter doi:10.1016/S1053-2498(03)00184-0
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STATISTICAL METHODS Survival rates were calculated using the Kaplan– Meier method1 and compared using the log-rank test. Multivariate analyses were performed using logistic regression analysis. Weights were used to account for incomplete follow-up. Patients with known status (e.g., alive or dead) at the timepoint of interest were assigned a weight of 1; patients with incomplete follow-up were assigned a weight proportional to the length of the interval for which their status was known. For example, in the analysis of survival within 1 year, if a patient were lost to follow-up at 9 months they would be assigned a weight of 0.75 in the multivariate analysis. The results of the multivariate analyses are reported as odds ratios (ORs) with either a corresponding pvalue and/or 95% confidence limits. Factors with an OR significantly greater than 1.0 indicate that the factor is associated with an increased likelihood of the event occurring. Conversely, an OR ⬍1.0 indicates that the event is less likely to occur when that factor is present.
HEART TRANSPLANATION Transplant Volumes and Indications There has been little change in the number of heart transplant procedures or in the breakdown of the ages of the recipients, as shown in Figure 1 The most common age for pediatric heart transplantation is between 0 and 1 year (Figure 2). This first year of life represents the greatest risk from congenital abnormalities of the cardiovascular system that are incompatible with life. There is an increasing number of transplants in the later teenage years as well. Figure 3 depicts donor data from the entire experience from 1982 through 2002; the distribution of donors for pediatric heart recipients follows the
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FIGURE 1 Age distribution of pediatric heart
recipients by year of transplant.
distribution for recipients closely. The majority of donors are within the first 1 or 2 years of life. After this period, the number of donors generally tapers down to the mid-teenage years. Finally, a fairly large number of donors from the adult age brackets have been utilized in pediatric heart transplantation. The proportion of infants requiring transplantation based on diagnosis is shown in Figure 4. For
FIGURE 2 Age distribution of pediatric heart recipients for transplants performed between January 1982 and June 2002.
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FIGURE 4 Diagnosis in pediatric heart transplant recipients (age ⬍1 year).
the total experience, approximately 75% of the infants are transplanted for congenital cardiac anomalies. This number decreased throughout the 1990s and has plateaued at about 60% since about 1999. Approximately 30% of infants have cardiomyopathy as the diagnosis leading to transplantation. For the childhood-age years (1 to 10 years of age) cardiomyopathy accounts for the majority of all heart transplants performed, but a balance has developed between patients with cardiomyopathy and those with congenital heart disease; this balance has been fairly stable over the last 3 years. The number of re-transplants remains small; only 5% of the patients transplanted in their childhood years have the diagnosis of re-transplantation. This is important, because the most common single age for transplant is ⬍1 year, and it is likely that the re-transplant population between the ages of 1 and 10 years received their primary heart transplant during infancy. The adolescent age group (11 to 17 years of age) continues to show a predominance of cardiomyopathic disease leading to transplant (Figure 6). Congenital heart disease is also common, and has accounted for approximately 25% of all adolescent transplants in the last 10 years. As noted in the other age groups, re-transplantation remains relatively uncommon and accounts for only 4% of adolescent heart transplants.
Immunosuppression
FIGURE 3 Age distribution for donors of pediatric heart recipients for transplants performed between January 1982 and June 2002.
The patterns of immunosuppressive agents used for pediatric patients in the recent era are shown in Figures 7 to 11. Figure 7 shows the percent of patients receiving induction immunotherapy. Almost 40% of patients currently receive some type of induction therapy. The most common agents are polyclonal anti-thymocyte preparation, used in about 25% of instances. The monoclonal antibody,
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FIGURE 5 Diagnosis in pediatric heart transplant
recipients (ages 1 to 10 years).
OKT3, was used in about 5% of patients and the interleukin-2 receptor (IL-2R) antagonist antibodies were used in approximately 10%. Figure 8 shows the pattern of induction immunotherapy, broken down by year. Overall, it appears that the use of IL-2R antagonist antibodies has been increasing with perhaps some reduction in the use of OKT3. The use of a polyclonal anti–T-cell antibody has
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FIGURE 8 Induction immunosuppression by year of
transplants in pediatric heart recipients for follow-ups between January 2000 and June 2002.
varied from 20% to approximately 33%, but there is no clear trend. Maintenance immunosuppression medications are shown in Figure 9, which displays the percent of patients who were on a given immunosuppressive agent at any time during the follow-up period between January 2000 and June 2002.
FIGURE 9 Maintenance immunosuppression at any
FIGURE 6 Diagnosis in pediatric heart transplant recipients (ages 11 to 17 years).
FIGURE 7 Induction immunosuppression in pediatric heart recipients for follow-ups between January 2000 and June 2002.
time during the follow-up period in pediatric heart recipients for follow-ups between January 2000 through June 2002.
FIGURE 10 Maintenance immunosuppression at time
of follow-up in pediatric heart recipients for follow-ups between January 2000 through June 2002.
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FIGURE 11 Maintenance immunosuppression drug
combinations at time of follow-up in pediatric heart recipients for follow-ups between January 2000 through June 2002.
Cyclosporine is still the primary T-cell activation inhibitor reported at both Years 1 and 5 and, by adding the columns for cyclosporine and tacrolimus, it appears that virtually all patients are maintained on one of these calcineurin inhibitors. The percent of patients reported to be on rapamycin remains extremely low. The use of mycophenolate mofetil (MMF) is more common in the first year than by the fifth year, and the percent of patients on azathioprine (AZA) is stable. Prednisone use is reported in about 75% of patients in the first year, whereas, by 5 years post-transplant, this decreases to approximately 40%. Figure 10 shows immunosuppression at the 1-year follow-up or 5-year follow-up as reported between January 2000 and June 2002. The data appear similar to those shown in Figure 9, although the percent of patients reported to be on MMF or prednisone at 1 year is lower than the cumulative exposure during the first year. The common combinations of immunosuppressive agents reported during Year 1 or Year 5 post-transplant are shown in Figure 11. In general, the combination of cycloporine or tacrolimus with MMF is less frequent in Year 5 than in Year 1. By 5 years, the percentage of patients with various other combinations or regimens increases to about 25%. The use of prednisone is not displayed in any of these combinations. As shown in Figures 9 and 10, very few patients are on rapamycin, and thus it is has not been included in the combinations. Obviously, many more combinations and permutations of immunosuppressive regimen are possible and are used in clinical practice; as more immunosuppressive agents become available these combinations will become even more complex. We hope to track outcomes as a function of immunosuppression; however, the small pediatric popu-
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FIGURE 12 Actuarial survival for pediatric heart
transplants performed between January 1982 and June 2001.
lation will make it difficult to detect minor differences in outcome.
Outcomes Survival. The actuarial survival for pediatric heart recipients is shown in Figure 12. There is a statistically significant difference in survival curves based on recipient age at the time of transplant, with the infant-age population having a greater early mortality than either of the older age groups. However, by 12 years post-transplant, both the childhood and adolescent survival curves have intersected the infant survival curves, indicating a lower rate of late mortality in the infant age group. In fact, the half-life for the infant age group is not computable, because, by 13 years, it has not penetrated the 50% survival barrier. For children at the ages of 1 and 10 years, the half-life is 12.4 years, based on the entire experience since 1982. For the adolescent age group, the half-life is 11 years. Figure 13 shows the conditional actuarial survival, which traces the subsequent survival for patients who have survived the
FIGURE 13 Actuarial survival, conditional on survival to 1 year, for pediatric heart transplants performed between January 1982 and June 2001.
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FIGURE 14 Actuarial survival by era for pediatric
heart transplants performed between January 1982 and June 2001.
first year after transplantation for the same patient cohort. There is a significant survival advantage for both the infant and childhood age ranges as compared with adolescents. However the lower rate of late mortality seen in both infant and childhood age ranges makes calculating a conditional half-life for these age brackets impossible at this time. The actuarial survival for pediatric heart recipients, broken down by era at transplantation, is shown in Figure 14. As noted in previous reports, survival has increased steadily with each era. The most recent era, from 1998 to 2001, was significantly different from any of the previous eras. The dramatic improvement with era is seen in the calculated half-life for patients transplanted between 1982 and 1987: The expected half-life was 6.6 years in the early 1980s, but for patients transplanted between 1988 and 1992 the half-life increased to 11.7 years. In the most recent era survival has continued to increase, but the half-life is not yet computable. Most of the improved survival appears to be evident within the first few months after transplantation, and probably reflects changes in techniques at the time of transplantation and in early immunosuppressive therapy. It is too early to tell whether there is a difference in late survival by era, but the slopes of the curves appear to be roughly parallel. An attempt to look at late survival in the most recent era is shown in Figure 15, in which conditional actuarial survival was broken down by age at the time of transplant. Thus, patients who survived to 1 year are subsequently followed to evaluate late survival, eliminating the impact of early post-transplant mortality. As can be seen in Figure 15 the curves are nearly identical. The infant and childhood age ranges tend to have somewhat better conditional survival until 4 years after transplantation, but these differences are not significant.
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FIGURE 15 Actuarial survival for recent era,
conditional on survival to 1 year, for pediatric heart transplants performed between January 1997 and June 2001.
A possible interplay between immunosuppressive regime and conditional actuarial survival for patients transplanted between April 1994 and June 2001 is shown in Figure 16. Because only about half of pediatric heart transplant recipients receive prednisone through the first year after transplantation, it is possible to look at survival as a function of this immunosuppressive agent. Figure 16 shows a significantly different survival curve based on long-term use of prednisone: Those patients who were either never given prednisone as part of maintenance immunosuppression and those initially started on prednisone and then discontinued before the first year have similar survival curves beyond the first year. However, the sub-group of patients receiving prednisone at the time of transplant and through the first year have lower subsequent survival. It is not clear whether this is a direct effect of the immunosuppressive agent, or a marker for other risk factors or management techniques. An analysis of survival was also performed for pediatric heart patients with a history of rejection during the first year after transplantation. Figure 17
FIGURE 16 Actuarial survival based on prednisone use for pediatric heart transplants performed between April 1994 and June 2001.
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FIGURE 17 Actuarial survival based on rejection
within Year 1 for pediatric heart transplants performed between April 1994 and June 2001.
shows the conditional actuarial survival beyond the first year after transplantation for patients who were free from rejection during the first year after transplantation compared to those with a history of rejection within the first year. There is a statistically significant difference in late survival based on history of rejection within the first year. A greater percentage of patients were reported to have rejection during the first year, but the population of patients in both groups is fairly large, making an analysis in survival difference robust; however, the actual difference in survival was ⬍10% by 8 years post-transplant.
Risk Factors for Mortality The diagnosis leading to transplantation continues to be a highly significant risk factor for mortality in the first year (Table I). The data from the current report mirrors the data in previous pediatric Registry reports, showing that congenital heart disease and diagnoses other than cardiomyopathy are associated with greater risks for 1-year mortality. The pre-transplant status of the patient, including the environment, are also risk factors, as reflected by the history of hospitalization and need for mechanical ventilation, which increases the risk for mortality. Continuous factors related to 1-year mortality in-
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FIGURE 18 Impact of recipient age on the odds of
mortality within 1 year for pediatric heart transplants performed between January 1995 and June 2001 (n ⫽ 2,055).
clude recipient age, bilirubin, serum creatinine and decreasing donor weight. The issue of donor weight is not related to the specific ratio between recipient and donor weight, but rather the absolute weight of the donor over the spectrum of pediatric recipients. The inverse relationship of mortality with absolute donor weight probably reflects the increased risk associated with younger age of the recipient and congenital diagnosis leading to transplant in the recipient. The relationship between recipient age and risk of 1-year mortality is shown in Figure 18. It is of interest to note that a similar U-shaped curve is seen in adult recipients as well, but there is no clear explanation for this finding. Figure 19 shows the relationship between serum creatinine at the time of transplantation and odds of 1-year mortality. The number of patients with high creatinine values is small and thus the p-value is of borderline statistical significance, but the relationship appears convincing. Creatinine potentially could serve as a quantifiable marker for risk at the time of transplantation. Among factors that were not significant in multivariate modeling for risk of 1-year mortality were the need for intravenous inotropes, prostaglandin infusion and extracorporeal membrane oxygenation
TABLE I Risk factors for mortality within 1 year for pediatric heart transplants performed between January 1995 and June 2001 (N ⫽ 2,055) Risk factor
Odds ratio
p-value
95% confidence interval
Congenital heart disease Other diagnosis (excluding cardiomyopathy and re-transplant) Hospitalized (including ICU) Ventilator
2.00 1.97 1.56 1.76
⬍0.0001 0.04 0.004 0.0008
1.53–2.62 1.02–3.82 1.16–2.10 1.26–2.44
ICU, intensive care unit.
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FIGURE 19 Impact of recipient creatinine on the odds
of mortality within 1 year for pediatric heart transplants performed between January 1995 and June 2001 (n ⫽ 2,055).
(ECMO) as well as a history of prior sternotomy or recent infection. Some of these factors were previously identified as risk factors, but in this most recent analysis the relationship was no longer observed. Donor factors not associated with 1-year mortality in the recipient include history of clinical infection, age and cause of death. Interestingly, donor/recipient combined factors not related to 1-year mortality included the donor/recipient weight ratio, cytomegalovirus (CMV) mismatch, ischemia
FIGURE 20 Impact of recipient creatinine on the odds of mortality within 5 years for pediatric heart transplants performed between January 1995 and June 1997 (n ⫽ 630).
time, HLA mismatches, panel-reactive antibody (PRA) and transplant center volume. The risk factors for 5-year mortality continue to include the need for a ventilator at the time of transplant, recipient age and serum creatinine. Prior sternotomy appears again as a risk factor for 5-year mortality, but may be influenced by the era during which the cohort was transplanted. The relationship between recipient serum creatinine and the odds of 5-year mortality is shown in Figure 17. As shown for 1-year mortality, serum creatinine has a direct relationship to the odds of 5-year mortality. The factors evaluated that were not related significantly to 5-year mortality for pediatric heart transplant recipients include the need for intravenous inotropic agents, need for ECMO, recent diagnosis of infection, and the need for hospitalization at the time of transplantation. Donor factors not significantly related to 5-year mortality include history of infection in the donor, gender, weight, age and cause of death. Transplant factors not significantly related to 5-year mortality include the donor/recipient weight ratio, CMV mismatch, ischemia time, HLA mismatch, PRA and transplant center volume. Because most of the mortality for pediatric recipients occurs in the early post-transplant period, the early mortality may overwhelm factors that could be related to 5-year mortality. To reduce this effect, an analysis was performed conditional on the survival of the patient to 1 year after transplantation. In this multivariate analysis, factors associated with 5-year mortality include re-transplantation, the need for intravenous inotropic medications at the time of transplantation, and treatment for rejection within the first posttransplant year (Table II). Interestingly, the need for prostaglandin infusion was also related to 5-year mortality. Prostaglandin infusion would be required in the sub-set of infants with ductal-dependent circulation. Often, these patients have hypoplastic left heart syndrome; previous Registry reports have shown patients with this condition to have a high
TABLE II Risk factors for mortality within 5 years, conditional on survival to 1 year, for pediatric heart transplants performed between January 1995 and June 1997 (N ⫽ 630) Risk factor
Odds ratio
p-value
95% confidence interval
Re-transplant Intravenous inotropes PGE Hospitalized for rejection or treated with anti-rejection medications between discharge and 1 year
4.68 2.06 4.05 2.39
0.003 0.01 0.03 0.003
1.68–3.01 1.19–3.56 1.15–14.25 1.36–4.19
PGE, prostaglandin estradiol.
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TABLE III Cause of death for pediatric heart transplant recipients for deaths between January 1992 and June 2002 Cause of death Coronary vasculopathy Acute rejection Lymphoma Malignancy, other CMV Infection, non-CMV Primary failure Graft failure Technical Other Multiple-organ failure Renal failure Pulmonary Cerebrovascular
0 to 30 days (N ⴝ 276)
31 days to 1 year (N ⴝ 231)
>1 year to 3 years (N ⴝ 147)
>3 years to 5 years (N ⴝ 93)
>5 years (N ⴝ 156)
2 (0.7%) 25 (9.1%)
21 (9.1%) 66 (28.6%) 5 (2.2%) 4 (1.7%) 5 (2.2%) 37 (16.0%) 12 (5.2%) 28 (12.1%) 3 (1.3%) 7 (3.0%) 23 (10.0%) 1 (0.4%) 12 (5.2%) 7 (3.0%)
32 (21.8%) 39 (26.5%) 8 (5.4%) 1 (0.7%)
35 (37.6%) 15 (16.1%) 2 (2.2%) 1 (1.1%)
54 (34.6%) 20 (12.8%) 14 (9.0%) 6 (3.8%)
11 (7.5%) 5 (3.4%) 25 (17.0%) 2 (1.4%) 8 (5.4%) 3 (2.0%)
5 (5.4%) 6 (6.5%) 17 (18.3%) 1 (1.1%) 4 (4.3%) 1 (1.1%)
5 (3.2%) 10 (6.4%) 30 (19.2%) 2 (1.3%) 8 (5.1%) 1 (0.6%)
7 (4.8%) 6 (4.1%)
5 (5.4%) 1 (1.1%)
4 (2.6%) 2 (1.3%)
1 (0.4%) 38 (13.8%) 44 (15.9%) 76 (27.5%) 17 (6.2%) 7 (2.5%) 24 (8.7%) 1 (0.4%) 22 (8.0%) 19 (6.9%)
CMV, cytomegalovirus.
risk of mortality, and survivors to have a possibly enduring detrimental legacy, a hypotheses that deserves further study.
Cause of Death Table III displays the causes of death for recipients of transplants between January 1992 and June 2002. Early graft failure is the leading cause of death and accounts for about 32% of deaths during the first 30 days. During the first year, acute rejection becomes the leading single cause accounting for almost 30% of deaths. It is likely that a percentage of patients listed as graft failure may also have had acute rejection. Between 1 and 3 years after transplantation, acute rejection continues to be the leading cause of death, occurring in approximately 25% of the patients, but coronary vasculopathy now accounts for about 20%, and there is a persistent incidence of graft failure that could represent either graft rejection or coronary vasculopathy. Beyond 3 years, acute rejection remains an important cause of death, but coronary artery vasculopathy is clearly the predominant cause of death, accounting for approximately 33% of all late deaths. Interestingly, graft failure continues to be represented in as many as 20% of patients at ⬎5 years post-transplant. This group of patients could represent biopsy-negative late acute rejection or undiagnosed coronary artery vasculopathy. Because of the multi-institutional nature of the Registry data, we are unable to tease out the causes of graft failure in this relatively large group of patients.
Specific Complications Table IV shows the cumulative prevalence of several morbid events in survivors during the first posttransplant year. As has been reported in previous Pediatric Registry reports, hypertension is the most common event and is found at some point during the first year in 44% of patients. Renal dysfunction remains infrequent, as do hyperlipidemia, diabetes and coronary vasculopathy (Table V). Cumulatively, hypertension is seen in 60% of patients within 5 years, but renal dysfunction remains relatively infrequent, and clearly significant levels of renal dysfunction are uncommon. Hyperlipidemia has a cumulative incidence of 17%, but diabetes remains infrequent, and in pediatric recipients coronary vas-
TABLE IV Post-transplant morbidity in pediatric heart transplant recipients within 1 year, based on follow-ups between April 1994 and June 2002: cumulative prevalence in survivors Outcome Hypertension Renal dysfunction Abnormal creatinine ⬍2.5 mg/dl Creatinine ⬎2.5 mg/dl Long-term dialysis Renal transplant Hyperlipidemia Diabetes Coronary vasculopathy
Within 1 year 44.2% (N ⫽ 1,507) 5.1% (N ⫽ 1,516) 3.2% 1.4% 0.5% 0.0% 8.6% (N ⫽ 1,578) 3.2% (N ⫽ 1,509) 2.5% (N ⫽ 1,363)
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TABLE V Post-transplant morbidity in pediatric heart transplant recipients within 5 years, based on follow-ups between April 1994 and June 2002: cumulative prevalence in survivors Outcome Hypertension Renal dysfunction Abnormal creatinine ⬍2.5 mg/dl Creatinine ⬎2.5 mg/dl Long-term dialysis Renal transplant Hyperlipidemia Diabetes Coronary vasculopathy
Within 5 years 60.0% (N ⫽ 365) 7.5% (N ⫽ 389) 5.9% 0.8% 0.8% 0.0% 17.1% (N ⫽ 398) 4.9% (N ⫽ 366) 11.4% (N ⫽ 228)
culopathy is reported in only 11% of survivors up to 5 years after transplantation. Actuarial freedom from coronary artery vasculopathy in pediatric heart recipients is shown in Figure 21. There is a steady decrease in freedom from coronary vasculopathy through at least 7 years post-transplant. However, over 75% of pediatric recipients remain free from vasculopathy at 7 years. Figure 22 shows the actuarial freedom from coronary vasculopathy as a function of age of recipient. Adolescent recipients appear to be at greater risk for vasculopathy and infants at the lowest risk for vasculopathy. Figure 23 displays survival after a diagnosis of coronary artery vasculopathy, according to recipient age. In contrast to Figure 22, infants appear to be at greatest risk for death after a diagnosis of coronary vasculopathy, with adolescent patients seemingly at lowest risk. However, by 2 years after diagnosis of vasculopathy, survival approaches 60% for all pediatric recipients. It is not clear whether these observations reflect differences in biology or differences in diagnostic technique. The infant age group would be the most
FIGURE 21 Freedom from CAV in pediatric heart
recipients for follow-ups between April 1994 and June 2002.
FIGURE 22 Freedom from CAV, stratified by age group, in pediatric heart recipients for follow-ups between April 1994 and June 2002.
difficult to diagnose in the early stages of vasculopathy, because angiography is the primary diagnostic test and the sensitivity of angiography in infants may be lower than in older recipients. Actuarial freedom from severe renal dysfunction, defined as creatinine ⬎2.5 mg/dl or the need for dialysis or renal transplant, is shown in Figure 24). Again, a steady decrease in freedom from severe
FIGURE 23 Survival after report of CAV, stratified by age group, in pediatric heart recipients for follow-ups between April 1994 and June 2002.
FIGURE 24 Freedom from severe renal dysfunction in pediatric heart recipients for follow-ups between April 1994 and June 2002.
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FIGURE 27 Age distribution of pediatric lung FIGURE 25 Freedom from malignancy in pediatric
heart recipients for follow-ups between April 1994 and June 2002.
renal dysfunction is evident through 7 years posttransplant, reflecting the known nephrotoxic effects of calcineurin inhibitors. The slope of the freedom from renal dysfunction curve is relatively flat, such that 90% of pediatric heart recipients are free of severe renal dysfunction at 7 years post-transplant. Figure 25 shows freedom from malignancy for pediatric heart recipients. It is evident from this figure that lymphoproliferative malignancies account for virtually all pediatric malignancies. A steady decrease in freedom from malignancy with time is noted for at least 7 years after transplantation. Fortunately, like renal dysfunction, the slope is relatively flat, and by 7 years 90% are free from malignancy. The functional status of pediatric heart recipients continues to be excellent, as shown in Figure 26. At all time periods after transplantation, ⬎95% of the surviving patients are reported to have no activity limitations. In summary, the pediatric heart transplantation data continue to document improving survival, primarily through a reduction in early mortality. Morbidity is most commonly represented in the form of
FIGURE 26 Functional status in pediatric heart
recipients for follow-ups between April 1994 and June 2002.
recipients by year of transplant.
hypertension, which has been shown in previous Registry reports to be related at least in part to prednisone use. Late survival is adversely influenced by acute rejection and the development of coronary vasculopathy. Repeat transplant procedures also increase the risk for late mortality and the development of coronary vasculopathy. Of the risk factors for early mortality, diagnosis, age, ventilator requirement, serum creatinine, and hospitalization at the time of transplant are significant contributors. Based on these observations we can begin to envision an unfortunate model patient at risk for early and late mortality. Perhaps the pediatric heart transplant community will be able to use this information to fashion strategies to reduce the risk of mortality and optimize the freedom from morbidity after pediatric heart transplantation.
LUNG TRANSPLANTATION Transplant Volumes and Indications The number of pediatric lung transplant procedures has decreased slightly since the late 1990s. As shown in Figure 27, the majority of recipients are still in the adolescent age range with most of the decline in number occurring in young children and infants. The age distribution of pediatric lung transplant recipients between 1988 and 2002 is shown in Figure 28. Most recipients were between 11 and 17 years of age, with the nadir between 2 and 7 years of age. Among younger aged pediatric recipients, the first year of life is the most likely time for lung transplantation. The indications for pediatric lung transplant recipients ⬍10 years of age are shown in Table VI. In the infant age group, congenital heart disease was the most common indication for lung transplantation, but thereafter the most common indication was cystic fibrosis. Primary pulmonary hypertension and congenital heart disease are the two other most common indications for younger children. Figure 29
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FIGURE 29 Diagnosis in 11- to 17-year-old pediatric
FIGURE 28 Age distribution of pediatric lung
lung recipients.
recipients for transplants performed between January 1986 and June 2002.
preparations. Figure 31 shows the maintenance immunosuppression administered to pediatric lung recipients at 1- and 5-year follow-up. The 1-year cohort shows a preponderance of tacrolimus as the primary calcineurin inhibitor, but for the 5-year cohort cyclosporine was most frequent. Rapamycin use remained low in both cohorts. There is an even breakdown between the use of MMF and AZA, and virtually all patients were on prednisone at both 1 and 5 years.
shows the diagnoses leading to pediatric lung transplantation for adolescent recipients. Cystic fibrosis has steadily increased as an indication leading to transplant and now accounts for about 67% of all adolescent lung recipients. The percentage of patients with primary pulmonary hypertension decreased during the 1990s, and overall accounts for approximately 10% of adolescent recipients.
Immunosuppression
Outcomes
Induction immunotherapy is used in a majority of pediatric lung recipients. Figure 30 shows the percent of patients receiving any induction therapy and a breakdown between polyclonal anti–T-cell preparations and IL-2R antagonist antibody preparations. The relative proportion of these agents has remained stable in the period between January 2000 through June 2002, with about 30% receiving IL-2R antagonists and roughly 20% polyclonal anti–T-cell
Survival. Figure 32 shows the actuarial survival by era for pediatric lung transplant recipients. Comparing the era of 1998 to 1992 to the most recent era of 1998 to 2001, there was no significant difference in actuarial survival. The half-life in the former era was 2.6 years, and in the latter was 3.1 years. The half-life for survival conditional upon surviving the first year was 8.2 years in the former era and 5.7
TABLE VI Indications for transplant in pediatric lung transplants performed between January 1991 and June 2002 Age < 1 year Indication Cystic fibrosis Primary pulmonary hypertension Congenital heart disease Idiopathic pulmonary fibrosis Pulmonary vascular disease Re-transplant: not obliterative bronchiolitis Re-transplant: obliterative bronchiolitis Obliterative bronchiolitis (not re-transplant) Bronchiectasis COPD/emphysema Other COPD, chronic obstructive pulmonary disease.
Age 1–10 years
N
%
7 20
17.1% 48.8%
5 3
12.2% 7.3%
6
14.6%
N
%
56 24 19 12 6 8 10 6 2 2 19
34.1% 14.6% 11.6% 7.3% 3.7% 4.9% 6.1% 3.7% 1.2% 1.2% 11.6%
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FIGURE 30 Induction immunosuppression in pediatric
lung recipients for follow-ups between January 2000 and June 2002.
years in the latter era. By 10 years after transplantation, the overall survival was ⬍40%. Figure 33 compares survival by age group for the period between January 1990 and June 2001, showing no significant difference. Figure 34 shows conditional actuarial survival according to age group; in this analysis, late survival depends on surviving to the
FIGURE 31 Maintenance immunosuppression at time of follow-up in pediatric lung recipients for follow-ups between January 2000 and June 2002.
FIGURE 32 Actuarial survival by era for pediatric lung transplants performed between January 1988 and June 2001.
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FIGURE 33 Actuarial survival by age group for
pediatric lung transplants performed between January 1990 and June 2001.
first year, and then subsequent analysis is performed. These survival curves are not significantly different, but there appears to be a trend toward increased survival in infants. This observation, if it strengthens with further analysis, would be similar to the observation seen in pediatric heart transplant recipients. Survival after pediatric lung transplantation may be influenced by the type of procedure, as shown in Figure 35. Actuarial survival was significantly better in patients receiving bilateral or double-lung transplants as compared with single-lung transplants. The inset demonstrates that the vast majority of pediatric recipients receive either bilateral or double-lung procedures. The diagnosis leading to transplantation appears to have a large effect on post-transplant survival, depending on the type of procedure performed. Figure 36 shows the actuarial survival for single- vs double-lung transplantation for patients with primary pulmonary hypertension. There is a highly significant difference in survival, but the number of patients is relatively small. Patients with primary pulmonary hyperten-
FIGURE 34 Actuarial survival by age group,
conditional on survival to 1 year, for pediatric lung transplants performed between January 1990 and June 2001.
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FIGURE 35 Actuarial survival by procedure type for
pediatric lung transplants performed between January 1990 and June 2001.
sion who received double-lung transplants had an actuarial survival at 10 years of approximately 50%, in contrast to patients who received a single lung and had an actuarial 10-year survival of approximately 10%.
Cause of Death Table VII displays the cause of death for pediatric
FIGURE 36 Actuarial survival by procedure type in
patients with primary pulmonary hypertension for pediatric lung transplants performed between January 1990 and June 2001.
lung recipients according to time since transplantation. In the 0- to 30-day post-transplant timeframe, graft failure is the leading cause of death, occurring in almost 50% of patients. In the period between 30 days and 1 year after transplantation, infections other than CMV account for 41% of deaths, easily the leading cause of death. Between 1 and 3 years post-transplant, bronchiolitis obliterans becomes the most common cause in 37% of patients, followed by infection other than CMV in 21%. Beyond 3 years, obliterative bronchiolitis remains the single most common cause of death, occurring in about 45% of patients. The trend toward increased death due to obliterative bronchiolitis mirrors the trend toward increasing cause of death in heart recipients due to coronary artery vasculopathy. Both of these phenomena likely represent rejection-related problems in the respective organs.
Specific Complications Morbidity is common after pediatric lung transplantation. Table VIII shows the cumulative incidence of a number of adverse outcomes in survivors between 1994 and June 2002. By 1 year post-transplant, 37% of patients are reported to have hypertension, increasing to 74% by 5 years. As in heart transplantation, renal dysfunction is uncommon by 1 year and significant renal dysfunction is infrequent. By 5 years, the percentage increases to 24%, and ⬎10% of survivors have creatinine ⬎2.5 mg/dl, long-term dialysis or renal transplantation. Hyperlipidemia is uncommon in the lung transplant population at both 1 and 5 years. Diabetes occurs in 20% of patients by 1 year and 31% of patients by 5 years. Previous analyses of Pediatric Registry data show a strong correlation between a diagnosis of cystic fibrosis and later development of diabetes after transplantation.
TABLE VII Cause of death for pediatric lung transplant recipients for deaths between January 1992 and June 2002 Cause of death Bronchiolitis Acute rejection Lymphoma CMV Infection, non-CMV Graft failure Cardiovascular Technical Other
0 to 30 Days (N ⴝ 45)
31 days to 1 Year (N ⴝ 75)
>1 year to 3 years (N ⴝ 81)
>3 years to 5 years (N ⴝ 35)
>5 years (N ⴝ 11)
30 (37.0%)
16 (45.7%) 1 (2.9%) 1 (2.9%)
5 (45.5%) 2 (18.2%)
6 (13.3%) 20 (44.4%) 6 (13.3%) 6 (13.3%) 7 (15.6%)
5 (6.7%) 3 (4.0%) 3 (4.0%) 5 (6.7%) 31 (41.3%) 14 (18.7%) 2 (2.7%) 1 (1.3%) 11 (14.7%)
17 (21.0%) 16 (19.8%) 2 (2.5%)
8 (22.9%) 3 (8.6%)
1 (9.1%) 2 (18.2%)
12 (14.8%)
6 (17.1%)
1 (9.1%)
4 (4.9%)
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TABLE VIII Post-transplant morbidity in pediatric lung transplant recipients within 1 year and within 5 years, based on follow-ups between April 1994 and June 2002: cumulative prevalence in survivors Outcome Hypertension Renal dysfunction Abnormal creatinine ⬍2.5 mg/dl Creatinine ⬎2.5 mg/dl Long-term dialysis Renal transplant Hyperlipidemia Diabetes Bronchiolitis obliterans
Within 1 year
Within 5 years
37.7% (N ⫽ 313) 7.6% (N ⫽ 315) 5.1% 1.6% 0.6% 0.3% 0.9% (N ⫽ 326) 21.0% (N ⫽ 314) 14.7% (N ⫽ 286)
73.7% (N ⫽ 57) 24.1% (N ⫽ 58) 12.1% 6.9% 3.4% 1.7% 1.7% (N ⫽ 59) 31.0% (N ⫽ 58) 20.5% (N ⫽ 39)
Bronchiolitis obliterans is a leading cause of late mortality after pediatric lung transplantation, and in survivors the cumulative incidence is 14.7% at 1 year, which increases to 20% by 5 years. Figure 37 displays the actuarial freedom from bronchiolitis obliterans for pediatric recipients; by 4 years, half of the pediatric recipients have experienced this morbid event. Figure 38 shows the actuarial freedom from significant renal dysfunction, defined as creatinine ⬎2.5 mg/dl, dialysis or renal transplant. More pediatric lung recipients are affected by significant renal dysfunction than pediatric heart recipients. This difference is probably a reflection of the increased immunosuppression used for lung transplant recipients as well as concomitant medications used to treat frequent infectious complications after lung transplantation. Figure 39 displays the freedom from malignancy in pediatric lung recipients. As is the case for heart recipients, lymphoproliferative abnormalities account for the vast majority of malignancies. By 6 years post-transplant, approximately 85% remain free from malignancy, slightly lower than that seen after heart transplantation.
Functional Status
FIGURE 37 Freedom from bronchiolitis obliterans in
FIGURE 39 Freedom from malignancy in pediatric
pediatric lung recipients for follow-ups between April 1994 and June 2002.
Re-hospitalization after lung transplantation is more common than after heart transplantation. However, with time, hospitalization becomes less frequent; most hospitalizations are either for infection alone or in combination with rejection. Figure 40 shows the breakdown in re-hospitalization by time post-transplant and by reason for hospitaliza-
FIGURE 38 Freedom from severe renal dysfunction in pediatric lung recipients for follow-ups between April 1994 and June 2002.
lung recipients for follow-ups between April 1994 and June 2002.
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FIGURE 40 Re-hospitalization post-transplant in
pediatric lung recipients for follow-ups between April 1994 and June 2002.
tion. Between 4 and 5 years, 60% of patients do not require hospitalization for management. Figure 41 displays the functional status of pediatric lung recipients as a function of time since transplantation. Greater than 80% of surviving patients are reported to have no activity limitations through 5 years post-transplant. Again, this is slightly lower than that seen after heart transplantation.
HEART AND LUNG TRANSPLANTATION Transplant Volumes and Indications The volume of pediatric heart–lung transplantation continued to decrease through 2001. Figure 42 shows the number of heart–lung transplant procedures performed by calendar year; the data are further sub-divided by age of the recipient. It can be seen that the number of infant and child recipients has decreased to negligible numbers, and even the number of adolescent recipients has decreased over time. The overall number of procedures performed worldwide in 2001 was approximately 10. Figure 43 shows the number of centers reporting pediatric heart–lung transplants, which has also fallen to approximately 10, indicating that, on average, only 1
FIGURE 41 Functional status in pediatric lung
recipients for follow-ups between April 1994 and June 2002.
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FIGURE 42 Age distribution of pediatric heart–lung recipients by year of transplant.
procedure is performed per center in a given year. Although the Registry will continue to monitor pediatric heart–lung transplant recipients, it is becoming a clinically insignificant activity. Figure 44 shows the number of pediatric heart–lung transplant recipients, broken down by recipient age. Based on the experience in the last 20 years it is clear that the majority of patients are in the adolescent age range. Figure 45 shows the diagnoses leading to pediatric heart–lung transplantation in adolescents; congenital heart disease and cystic fibrosis were the most com-
FIGURE 43 Number of centers reporting pediatric heart–lung transplants.
FIGURE 44 Age distribution of pediatric heart–lung
recipients for transplants performed between January 1982 and June 2002.
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FIGURE 45 Diagnosis in 11- to 17-year-old pediatric heart–lung transplant recipients.
mon diagnoses leading to pediatric heart–lung transplantation. A trend analysis from 1986 to 2001 is shown at the bottom of Figure 45 for the 3 most common indications leading to transplant; congenital heart disease has remained relatively stable, whereas there were large fluctuations in primary pulmonary hypertension and cystic fibrosis. These fluctuations are primarily due to the small number of recipients, and overall there has not been a dramatic change in the relative percentages of these 3 diagnoses.
Survival Survival after pediatric heart–lung transplantation is shown in Figure 46. There was no significant difference in survival among recipients between 1 and 10 years of age vs the adolescent age range of 11 to 17 years. The calculated half-life for the 1- to 10-yearold age range is 2.0 years, and in the 11- to 17-yearold age range it is 3.3 years. By 10 years after transplantation, the overall survival is approximately 20%. In Figure 47, an era analysis is shown, comparing actuarial survival of pediatric heart–lung transplant recipients vs the era of transplantation. Unlike heart transplant recipients, there is no era
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FIGURE 47 Actuarial survival by era for pediatric
heart–lung transplants performed between January 1982 and June 2001.
effect for heart–lung recipients (Figure 47). In fact, the calculated half-life for the most recent era between 1998 and 2001 is 2 years, which is the lowest for any of the eras evaluated. The conditional half-life for the most recent era is only 3.3 years, which is also the lowest for any of the eras evaluated. This failure to improve survival with time may reflect the diminishing experience available, with most institutions now doing no more than 1 procedure in a given year. These data are difficult to interpret because the numbers are so small; however, the survival curve suggests that a careful re-evaluation of pediatric heart–lung transplantation may be in order. Table IX shows the causes of death after pediatric heart–lung transplantation. As demonstrated in previous years, these data are comparable to those seen after lung transplantation. Graft failure explains 50% of the mortality within the first 30 days, and at ⬎1 year bronchiolitis obliterans accounts for approximately 50% of mortality. Because the number of pediatric heart–lung transplant procedures has become so small and the mortality remains high, an analysis of morbidity was not performed.
CONCLUSIONS
FIGURE 46 Actuarial survival for pediatric heart–lung transplants performed between January 1982 and June 2002.
The number of pediatric heart and lung transplant procedures has remained relatively stable in comparison to recent years. The outcomes for heart transplantation have improved steadily, primarily through a reduction in early mortality. A more thorough analysis of the associated risk factors for early and late mortality and a more thorough analysis of the risk of coronary vasculopathy have been included in this report, as compared with previous years. Coronary vasculopathy is a major cause of late graft failure, and a more thorough understand-
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TABLE IX Cause of death for pediatric heart–lung transplant recipients for deaths between January 1992 and June 2002 Cause of death Bronchiolitis Acute rejection Infection, other Graft failure Technical Other
0 to 30 days (N ⴝ 20)
31 days to 1 year (N ⴝ 24)
>1 year to 3 years (N ⴝ 25)
>3 years to 5 years (N ⴝ 16)
>5 years (N ⴝ 16)
13 (52.0%)
8 (50.0%)
4 (25.0%)
5 (25.0%) 10 (50.0%) 3 (15.0%) 2 (10.0%)
1 (4.2%) 1 (4.2%) 9 (37.5%) 5 (20.8%) 1 (4.2%) 7 (29.2%)
5 (20.0%) 5 (20.0%)
1 (6.3%) 5 (31.3%)
5 (31.3%) 5 (31.3%)
2 (8.0%)
2 (12.5%)
2 (12.5%)
ing and management of this condition will be necessary if we are to see reductions in late mortality similar to those seen with early mortality. Infant recipients seem to be at lower risk for late graft vasculopathy in heart recipients and bronchiolitis obliterans in lung recipients. Pediatric heart–lung transplantation continues to decrease in frequency
and survival rates appear to be decreasing as well. Thus, the ongoing role of this procedure in the management of irreversible pediatric cardiopulmonary disease seems uncertain. The authors wish to thank Dawn Schmeck and Shari Borcherding for assistance in preparing the manuscript.