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The Registry of the International Society of Heart and Lung Transplantation: Third Official Pediatric Report-1999
REGISTRY
The Registry of the International Society of Heart and Lung Transplantation: Third Official Pediatric Report-1999 Mark M. Boucek, MD, Albert Faro, MD, Richard J. Novick, MD, Leah E. Bennett, PhD, Bennie Fiol, BS, Berkeley M. Keck, MPH, and Jeffrey D. Hosenpud, MD
T
he Third Pediatric Report of the Registry of the International Society of Heart and Lung Transplantation provides additional analyses of the experience during the first two decades of pediatric heart transplantation (1983 through 1998). The pediatric data are a subset of the entire Registry of thoracic transplantation but are important and biologically unique and can serve as a comparison to the overall experience. The patient population analyzed spans a period from the beginnings of pediatric heart transplantation in the early 1980’s. The current data indicates a recent trend toward improving survival. Further comparisons of patients with a congenital diagnosis leading to transplantation versus the diagnosis of cardiomyopathy provides a further insight into the risk of early mortality. The data also shows a relatively low annual risk of death in children transplanted under 10 years of age and followed for more than 3 years post heart transplantation. In this report, we continue the analysis of morbidity and its possible relation to immunosuppressive medications. Furthermore, for the first time, we have begun an analysis of the impact of thoracic organ trans-
From the International Society for Heart and Lung Transplantation, Dallas, Texas Submitted October 18, 1999; accepted October 22, 1999. Reprint requests: International Society for Heart and Lung Transplantation, 14673 Midway Road, Suite 108, Dallas, TX 75244 J Heart Lung Transplant 1999;18:1151–1172. Copyright © 1999 by the International Society for Heart and Lung Transplantation. 1053-2498/99/$–see front matter PII S1053-2498(99)00114-X
plantation on the critical pediatric outcome measure of growth.
DATA SET AND STATISTICAL METHODS The 1999 Pediatric Report contains world–wide data on 4,178 heart, 411 heart-lung, and 525 lung (single or double) transplantations performed through 1998. The data collection for the calendar year 1998 however is still being completed, and additional data will likely be presented in the next Pediatric Registry Report. The number of centers which have contributed to the data reported for the individual thoracic organ transplants include 208 heart, 65 heart–lung, 37 single lung, and 62 bilateral/ double lung transplantation centers. The univariate survival curve analysis and multivariate logistic regression methods were reported in the Second Official Pediatric Report.1
HEART TRANSPLANTATION The actual number of pediatric heart transplantations performed in 1997 was virtually identical to 1996. It is likely that for 1998, when data collection is completed, the number of transplants will be in the same range and continues a plateau phenomenon which began in the early 1990’s.1 The shaded bars in Figure 1 indicate the number of heart transplantations performed in the indicated year (Y1 axis), and the solid line indicates the number of centers reporting transplantations in each year (Y2 axis). In contrast to the plateau in the number of pediatric patients undergoing heart transplantation, the previously noted downward trend in the number 1151
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FIGURE 1 Pediatric heart transplantation volume and number of centers by year. of centers has continued with over a 20% reduction from the peak in 1994. A similar number of centers were reporting data in 1988 as in 1998. In comparison to the reduction in center numbers there was a 63% increase in the number of heart transplants performed between 1988 and 1998. These data
indicate a further concentration of the experience in pediatric heart transplantation and on average would represent the experience increasing from approximately 2.6 transplantations per center to 4.4 transplantations per center in 1998. Figures 2, 3, and 4 show the indications for heart transplantation.
FIGURE 2 Pediatric heart transplantation indications for recipients ⬍1 year of age. Retx ⫽ re–transplantation.
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FIGURE 3 Pediatric heart transplantation indications for recipients 1–10 years of age. Retx ⫽ re–transplantation.
These figures also include trend data for the two most common indications, myopathy and congenital heart disease in the lower panel. Figure 2 displays the indications for children ⬍1 year of age at the
time of transplant. Figure 3 represents children age 1–10 years, and Figure 4 for adolescents aged 11–17. There has been little change in the indications for transplantation over time. In the infant age group
FIGURE 4 Pediatric heart transplantation indications for recipients 11–17 years of age. Retx ⫽ re–transplantation.
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FIGURE 5 Pediatric heart transplantation actuarial survival (1982–1998). (⬍1 year), a diagnosis of congenital heart disease accounts for approximately 70% of the indications. In children age 1–10 years of age there is a relatively equal distribution between myopathy and congenital diagnosis whereas in the adolescent ages about 2⁄3 of the patients had myopathy and 1⁄3 had a congenital diagnosis. Interestingly, re–transplantation accounts for ⬍5% of all transplants in all ages. Figure 5 shows the actuarial survival for pediatric heart transplant recipients from 1982 through 1998. The conditional half-life for all pediatric heart transplant recipients is now ⬎14 years. The conditional (surviving the first year post transplant) half–life has increased 1.4 years since the 1998 Pediatric Report. In Figure 6 the actuarial survival for pediatric recipients is broken down into three eras for comparison. The era 1998 through 1991 is shown as triangles, the era 1992 through 1994 as open circles, and the era 1995 through 1998 as open squares. In the First Pediatric Registry Report there was no real era effect noted in the pediatric population through 1996. With the most recent data there is a significant improvement in survival in the most recent era. Coupling the overall expected conditional half–life with the recent improvement noted in the current era, decades long survival for pediatric heart transplant recipients seems likely. Still the number of patients at 13 years post transplant is relatively small. Additional longitudinal follow– up will provide a greater number of patients and more accuracy about long–term predictions. Figure 7 compares the
actuarial survival of pediatric recipients who underwent transplantation for the diagnosis of cardiomyopathy versus the age of the recipient. The largest number of patients are in the adolescent age group which mirrors the indications for transplantation of adolescents. There was no significant difference in the actuarial survival of patients transplanted for cardiomyopathy between the different age groups. On Figure 8 the actuarial survival for patients undergoing transplantation with the diagnosis of congenital heart disease is broken down by the age of the recipient. In contrast to the data shown for patients with cardiomyopathy, the largest number of patients is now in the ⬍1 year group which again reflects the indications for transplantation in this younger aged population. It is evident that there was an increased early mortality when the diagnosis leading to transplantation was congenital heart disease, which is most striking in the infant age group. There is a significant difference in mortality overall for the youngest recipients vs. the adolescent recipients noted primarily in the early post transplant time. However, by seven years the survival is virtually identical for all age ranges, which can be explained by the low decremental slope for the survival curve of infant age recipients. The risk factors by multivariate analysis for one year mortality after pediatric heart transplantation are shown in Table I.2 Repeat transplantation remains the variable with the highest risk for one year mortality followed by assist device support, ventila-
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FIGURE 6 Pediatric heart transplantation actuarial survival by era. tor support, and a diagnosis of congenital heart disease. As mentioned earlier transplantation during the most recent era is associated with a lower risk for one year mortality. The cause of death as a function of time in pediatric recipients following
heart transplantation is shown in Figure 9. In the early post transplant period, acute graft failure and cardiac failure remain the most common causes of death. During the first year acute rejection followed by infection are the two most common causes of
FIGURE 7 Pediatric heart transplantation actuarial survival (diagnosis of cardiomyopathy).
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FIGURE 8 Pediatric heart transplantation actuarial survival (diagnosis of congenital heart disease).
death. Between one and 3 years acute rejection followed by chronic rejection (which includes coronary artery disease) has become the two most common causes of death. When death occurs after 3 years, chronic rejection and coronary artery disease accounts for close to half of the late deaths with acute rejection still a persisting threat. Malignancy has remained an infrequent cause of death throughout all time periods including after 3 years. As noted in the previous Pediatric Registry Reports, there is still a large minority of patients whose cause of death does not fit into any frequently defined cate-
TABLE I Pediatric heart transplantation risk factors for 1 year mortality
Variable Repeat TX Balloon or VAD Ventilator Diagnosis ⫽ Congenital Heart Year of TX ⫽ 1995–1997 N ⫽ 3,199
Odds Ratio
P-value
95% Confidence Interval
2.11 1.99 1.56 1.44
0.004 0.003 0.0002 0.0002
1.28–3.50 1.27–3.12 1.24–1.97 1.19–1.75
0.68
0.0003
0.55–0.84
gory and is therefore categorized as “other”. These patients died largely from cerebrovascular accidents and nonspecific cardiovascular death. Nonspecific cardiovascular death may be in part explained by chronic rejection if more detailed data was available. The impact of rejection occurring during the first year post transplant on subsequent late survival is shown on Figure 10. The graph compares actuarial survival for two groups of patients (with or without rejection) who survived the first year. Patients with a history of rejection during the first year had a significantly greater mortality in subsequent years. Patients (shown in triangles) who were free from rejection and survived the first year had a significantly greater survival at 4 years, with a very flat curve indicating minimal yearly attrition. The data stops at 4 years in the free from rejection group since there are no other deaths as yet reported. We also looked at the risk of developing coronary artery disease late in patients surviving the first year according to the rejection experience during the first year. The data in Table II show that if rejection was present in the first year, there was a significantly higher risk of developing coronary artery disease at 2 year and 3 year follow– up (p ⬍ .05). Unfortunately, there is also a fairly large percentage of
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FIGURE 9 Pediatric heart cause of death. patients with incomplete data as shown in Table II. The largest unknown group were those in whom the rejection status was not specified. As seen in Figure 9, late mortality is most likely to be associated with chronic rejection/coronary artery
disease. The overall incidence of coronary artery disease is low; however, it should be noted that in pediatric patients the diagnosis is made predominantly with angiography which has been shown to under represent the true incidence of coronary
FIGURE 10 Heart transplantation actuarial survival versus rejection.
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TABLE II Post heart transplantation coronary artery disease (CAD) (US: April 1994 –Dec. 1998) Rejection in First Year
CAD ⴝ Unknown
CAD ⴝ No
CAD ⴝ Yes
CAD ⴝ Unknown
CAD ⴝ No
CAD ⴝ Yes
Yes No Unknown
30.3% (n ⫽ 86) 14.8% (n ⫽ 40) 55.9% (n ⫽ 447)
62.3% (n ⫽ 177) 82.6% (n ⫽ 223) 42.6% (n ⫽ 341)
7.4% (n ⫽ 21) 2.6% (n ⫽ 7) 1.5% (n ⫽ 12)
26.4% (n ⫽ 56) 9.3% (n ⫽ 13) 49.4% (n ⫽ 388)
66.0% (n ⫽ 140) 85.7% (n ⫽ 120) 47.6% (n ⫽ 374)
7.5% (n ⫽ 16) 5.0% (n ⫽ 7) 3.1% (n ⫽ 24)
2 Year Follow–up
3 Year Follow–up
artery disease. Overall when one looks at the cause of death in Figure 9, the impact of early rejection on late survival as shown in Figure 10, and finally the impact of early rejection on the subsequent development coronary artery disease as shown in Table II the importance of early graft rejection in subsequent patient survival is obvious. The maintenance immunosuppressive medications for pediatric recipients at the time of discharge, at one year and at 3 years post transplant are indicated on Figure 11. This year, for the first time, we have included data on mycophenolate mofetil (MMF). As reported previously all patents essentially receive a T– cell activation inhibitor with approximately 80% receiving cyclosporine at all time periods. The percent receiving tacrolimus has increased from the previous Report and is now greater than 20% at 3 years. Antiproliferative therapy in the form of azathioprine or MMF initially is used in virtually all patients, but by 3 years this number had been reduced to approximately 75%. The pediatric
population continues to provide a unique look at immunosuppressive therapy since by 3 years post transplant only 50% of patients remain on prednisone. This percent is reduced from approximately 75% at the time of transplant and less than 70% at one year. The pediatric population therefore provides an opportunity to evaluate the effect of prednisone use on survival and morbidity. As shown in Figure 11, 2⁄3 of the patients surviving to 1 year were on prednisone and 1⁄3 were off prednisone by 1 year. Figure 12 shows the actuarial survival curves for two groups of patients differentiated by whether or not they were still on prednisone at 1 year. Only patients surviving to 1 year were included in the analysis. The triangles represent those patients not on prednisone at 1 year and the open circles those on prednisone at 1 year. The curves are similar; however, the patients not on prednisone at 1 year had a significantly greater actuarial survival. This data does not evaluate subsequent prednisone use, and it is possible that there
FIGURE 11 Pediatric heart transplantation maintenance immunosuppression.
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FIGURE 12 Pediatric heart transplantation actuarial survival versus prednisone. was crossover between the two groups after the 1 year point in time. This data can only be interpreted as the affect of prednisone use in the first year and ideally cummulative prednisone dose should be evaluated. There may also be an adverse patient selection bias since patients at increased risk of rejection may have been left on or started on prednisone and thus may be expected to have a higher subsequent risk. As the cohort of patients (with more detailed data) transplanted between April 1994 and December 1998 grows, the inter– relation of factors such as rejection and prednisone use on outcomes will be looked at in future years in a multi–variate approach. A similar analysis of the use of prednisone in the first year, defined as patients still on prednisone at one year, on the subsequent development of coronary artery disease is shown in Table III. There was a significant (p ⬍ .05) increase in coronary artery disease for the group of patients still on prednisone
at 1 year. Like the analysis of rejection in the first year and the impact on subsequent coronary artery disease, there are a large number of patients where the data is incomplete. This data may reflect a selection process such that those patients still on prednisone at one year may represent a higher risk group for rejection, and therefore one would expect a higher risk of subsequent coronary artery disease. This data will be evaluated further in future reports. Table IV shows the most common morbidities following pediatric heart transplantation for the subset of US patients between April 1994 and December 1998 at 1 and 3 years post transplant. As has been reported in previous Pediatric Registry Reports, hypertension remains the most common diagnosis postoperatively. Approximately 40% of patients are categorized as being hypertensive. At 1 year 5% are reported to be hyperlipidemic, 3.2% diabetic, and 1.4% with a malignancy. These percentages increased slightly by the 3 year follow– up.
TABLE III Post heart transplantation coronary artery disease (CAD) (US: April 1994 –Dec. 1998) Prednisone in First Year
CAD ⴝ Unknown
CAD ⴝ No
CAD ⴝ Yes
CAD ⴝ Unknown
CAD ⴝ No
CAD ⴝ Yes
Yes No Unknown
32.2% (n ⫽ 241) 44.2% (n ⫽ 170) 73.6% (n ⫽ 162)
63.6% (n ⫽ 476) 54.5% (n ⫽ 210) 25.0% (n ⫽ 55)
4.3% (n ⫽ 32) 1.3% (n ⫽ 5) 1.4% (n ⫽ 3)
25.8% (n ⫽ 150) 30.9% (n ⫽ 97) 86.8% (n ⫽ 210)
67.7% (n ⫽ 394) 66.6% (n ⫽ 209) 12.8% (n ⫽ 31)
6.5% (n ⫽ 38) 2.5% (n ⫽ 8) 0.4% (n ⫽ 1)
2 Year Follow–up
3 Year Follow–up
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TABLE IV Post heart transplantation (April 1994 –Dec. 1998) 1 Year Followup HTN Hyperlipidemia Diabetes Malignancy Renal Dysfunction
No Renal Dysfunction
% 42.5 5.0 3.2 1.4 95.0
No Renal Dysfunction
% 36.8 9.4 2.7 2.0 95.7
Renal Dysfunction Creatinine ⬎ 2.5 mg/dl Chronic Dialysis
2.6 1.8 0.5
Renal Dysfunction Creatinine ⬎ 2.5 mg/dl Chronic Dialysis
3.3 1.0 0.0
Renal dysfunction, however, remains very uncommon with 95% of patients at 1 year and 3 years reporting no renal dysfunction. Table V displays an analysis of the presence or absence of hypertension according to the immunosuppressive medications for heart transplant recipients. There was a significant association between prednisone as a maintenance immunosuppressive agent and the presence of hypertension. There was no relationship between cyclosporine use and hypertension despite a significant relationship between tacrolimus and hypertension. This data is similar to the data shown in the Second Pediatric Registry Report. The quality of life of pediatric recipients can be reflected in their rehospitalization rate and functional status. Figure 13 shows that a slight majority of patients at one year follow– up have not required hospitalization since transplant. The most frequent indication for rehospitalization was rejection or infection. However, by 3 year follow– up 70% of patients were free from hospitalization during that year. Of those hospitalized, infection and rejection were nearly equal as the cause for readmission. Figure 14 shows the functional status for pediatric heart transplant recipients for the US subset be-
TABLE V Post heart transplantation drug treated hypertension (HTN) (April 1994 –Dec. 1998) % developing HTN by 3-year follow-up
Immunosuppression at 1 year Not on immuno. On immuno. p-value Cyclosporine Azathioprine Prednisone Tacrolimus
3 Year Followup
46.9% 28.6% 15.7% 33.3%
34.4% 37.6% 45.5% 54.8%
0.17 0.24 0.001 0.019
tween April 1994 and December 1998. More than 90% of patients were felt to have no activity limitation with only approximately 5% of patients requiring some form of assistance. In pediatric patients’ rehabilitation can also be assessed by growth parameters. Tables VI and VII show the height and weight for pediatric heart transplant recipients respectively. This data was for the US subgroup of patients transplanted between April 1, 1994 and December 31, 1997. They were broken down into four age groups: less than 1 year, 1–5 years, 6 –10 years, and 11–17 years, and only the data for the groups 1–5 years and 11–17 years were shown. The mean age, number of transplants with follow– up, and number with known height or weight parameters and the actual mean height and weight in centimeters or kilograms is displayed for the time at listing, pretransplant, 1 year follow– up, 2 year follow– up, and 3 year follow– up. A spurt in growth is evident in the year following transplant for all age groups except the adolescent age groups where there was no incremental increase in height parameters despite a mean age of 14.5 years at the time of listing. On average a growth of approximately 4 cm per year would have been expected for adolescents in this age range. In the younger age groups, the growth spurt following transplantation appeared to be sustained in subsequent years. The explanation for the lack of growth in adolescents following transplantation is uncertain. The 1999 report for pediatric heart transplantation is encouraging with an improving short term and long term actuarial survival, and other than hypertension, low morbidity and excellent rehabilitation. The analysis of mortality again indicates the important role of rejection. Rejection in the first year appears to be an indicator for subsequent events such as coronary artery disease and late mortality.
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FIGURE 13 Rehospitalization post pediatric heart transplantation.
LUNG TRANSPLANTATION The overall number of lung transplantations performed in pediatric patients has remained stable since 1995. Similar to heart transplantation there appears to be a reduction in the number of centers performing lung transplant procedures but with a
stabilization of the overall number of procedures performed. Figure 15 shows a graphic display of the number of lung transplants (vertical bars) by year with the solid line (Y2 axis) representing the number of centers. The indications for lung transplantation in the two youngest age groups are shown in Figure
FIGURE 14 Functional status post pediatric heart transplantation.
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TABLE VI Post heart transplantation: height statistics (Transplants: April 1994 –Dec. 1997)
Age group
1–5
11–17
Time point
Mean Age
N of Transplants/ follow-ups
N with known height
Mean (cm)
Std. Dev.
Listing Pre-transplant 1-year follow-up 2-year follow-up 3-year follow-up Listing Pre-transplant 1-year follow-up 2-year follow-up 3-year follow-up
2.77 2.97 4.07 5.10 6.03 14.45 14.72 15.70 16.50 17.65
226 226 165 138 96 311 311 258 212 137
194 175 156 88 50 291 272 165 101 37
87.3 88.3 95.1 105.1 109.1 158.1 159.1 159.4 159.8 159.2
14.2 14.0 12.2 13.0 13.7 15.8 15.4 14.0 13.4 13.7
16. In the infant age group congenital anomalies followed by chronic lung disease (CLD) are the two single most common indications but a large group of patients do not fit into any clear diagnostic category and are included in the other category. In the age group of 1–10 years cystic fibrosis makes an appearance as the most common single indication followed by primary pulmonary hypertension and interestingly retransplantation. Figure 17 shows the indications for the lung transplantation adolescent age group. In adolescents, cystic fibrosis is the most common indication for lung transplant, accounting for over 60% of patients. The indication for lung transplantation as a function of year of transplant is shown at the bottom of this Figure with cystic fibrosis represented by triangles, primary pulmonary hypertension as the solid squares, and idiopathic pulmonary fibrosis as the crossed points. Cystic fibrosis has accounted for the majority of lung
transplantations from 1993 onward and the percent has remained relatively stable. The actuarial survival of all pediatric lung transplant recipients from 1982–1998 is shown on Figure 18. A total of 486 patients are included in the Registry, and the survival half–life remains around 4.2 years which is comparable to that reported in the Second Pediatric Registry Report. The conditional half–life, which discounts for the high early mortality, was 6.8 years. By 6 years, post transplant there is about a 40% survival. Figure 19 breaks down the actuarial survival following lung transplantation for three periods of time. The 1988 –1991 data are shown in the triangles with the era 1992–1994 in the open circles and the era 1995–1998 as the open squares. There is a significant difference comparing survival in the most recent period from 1995–1998 to either of the earlier periods. This is the first time that we have documented an era effect on survival
TABLE VII Post heart transplantation: weight statistics (Transplants: April 1994 –Dec. 1997)
Age group
1–5
11–17
Time point
Mean Age
N of Transplants/ follow-ups
N with known weight
Mean (kg)
Std. Dev.
Listing Pre-transplant 1-year follow-up 2-year follow-up 3-year follow-up Listing Pre-transplant 1-year follow-up 2-year follow-up 3-year follow-up
2.77 2.97 4.07 5.10 6.03 14.45 14.72 15.70 16.50 17.65
226 226 165 138 96 311 311 258 212 137
211 187 127 92 55 294 279 185 111 45
11.9 12.1 16.2 18.1 19.5 51.4 51.6 60.4 60.5 62.0
4.2 3.9 5.4 6.4 6.3 18.5 17.9 21.0 20.4 19.3
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FIGURE 15 Pediatric lung transplantation volume and number of centers by year. after pediatric lung transplantation and is comparable to what has become evident in heart transplantation. The causes of death following lung transplantation are shown in Figure 20. The different pie diagrams represent the time post transplant. In the initial 30 days acute graft failure has remained the most common cause of death. Following the first
month, infection is the greatest risk to patient survival; in the period of 1–3 years and beyond chronic rejection/bronchiolitis becomes the dominant factor. Like the previous reports, it was clear that in the first year acute graft failure and infection were most likely to be the cause of death while later the sequelae of chronic rejection became the most common cause of mortality. Figure 21 shows the
FIGURE 16 Pediatric lung transplantation indications for recipients ⬍1 year of age and 1–10 years of age. Retx ⫽ re–transplantation.
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FIGURE 17 Pediatric lung transplantation indications for recipients 11–17 years of age. Retx ⫽ re–transplantation.
actuarial survival curves for the US subset of patients since 1984. Patients who survived the first year post transplant were evaluated in terms of their late survival according to whether they experienced acute rejection during the first year. The survival curve is normalized to 100% at 1 year. The subsequent curves show the patients free from rejection in the first year with triangles and those with rejection
in the first year shown as open circles. Within the subsequent years there is no significant difference in mortality for pediatric lung transplant recipients which is in contrast to heart transplant recipients. Figure 22 shows the immunosuppressive medications used following lung transplantation. This year, we have included the use of mycophenolate mofetil (MMF). Most patients remained on prednisone as
FIGURE 18 Pediatric lung transplantation actuarial survival (1982–1998).
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FIGURE 19 Pediatric lung transplantation actuarial survival by era. well as a T– cell activation inhibitor, either cyclosporin or tacrolimus, and an anti-proliferative agent in the form of MMF or azathioprine through year 3. The use of tacrolimus appears to have plateaued at around 20% which is comparable to the previous report. Table VIII shows the morbidity following
lung transplantation. Like after heart transplantation, hypertension is the most common form of morbidity, with an increase in incidence to 53% by 3 years. Diabetes was present in about 15% of patients at both 1 year and 3 years follow– up. Table IX shows the breakdown of patients with
FIGURE 20 Pediatric lung transplant cause of death by time after transplantation.
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FIGURE 21 Pediatric lung transplantation actuarial survival versus rejection. diabetes as a function of whether the indication for transplantation was cystic fibrosis or not. A large number of patients are lacking data on the presence or absence of diabetes. However, in those patients where diabetes was either reported as a positive finding or negative finding, there was a highly significant association with the diagnosis of cystic fibro-
sis at both 1 and 3 years follow– up. In the patients without cystic fibrosis only 1% were reported to have diabetes whereas in those patients with cystic fibrosis 21% were reported to have diabetes. Renal function has remained satisfactory with only 4% of patients reporting renal dysfunction at 3 years follow– up. Figure 23 shows the functional status of
FIGURE 22 Pediatric lung transplantation maintenance immunosuppression.
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TABLE VIII Post lung transplantation (April 1994 –Dec. 1998) 1 Year Follow–up HTN Hyperlipidemia Diabetes Malignancy Renal Dysfunction
3 Year Follow–up % 32.7 0.6 17.2 7.6 93.6 2.9 1.2 2.3
No Renal Dysfunction Renal Dysfunction Creatinine ⬎ 2.5 mg/dl Chronic Dialysis
% 53.2 0.0 14.9 2.1 93.6 4.3 2.1 0.0
No Renal Dysfunction Renal Dysfunction Creatinine ⬎ 2.5 mg/dl Chronic Dialysis
TABLE IX Post heart transplantation: Relationship of diabetes to diagnosis of cystic fibrosis (April 1994 –Dec. 1998) 1-year follow-up
3-year follow-up
Diabetes Status
Cystic Fibrosis ⴝ No
Cystic Fibrosis ⴝ Yes
Total
Cystic Fibrosis ⴝ No
Cystic Fibrosis ⴝ Yes
Total
Not Reported No Yes Total
120 (59.1%) 81 (39.9%) 2 (1.0%) 203 (100.0%)
42 (32.8%) 59 (46.1%) 27 (21.1%) 128 (100.0%)
162 (48.9%) 140 (42.3%) 29 (8.8%) 331 (100.0%)
18 (40.9%) 25 (56.8%) 1 (2.3%) 44 (100.0%)
1 (4.8%) 15 (71.4%) 6 (27.3%) 21 (100.0%)
19 (28.8%) 40 (60.6%) 7 (10.6%) 66 (100.0%)
Test of relationship between cystic fibrosis (No or Yes) and diabetes (No or Yes): at 1 year, p ⬍ 0.0001; at 3 years, p ⫽ 0.035
FIGURE 23 Functional status post pediatric lung transplantation.
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FIGURE 24 Pediatric heart–lung transplantation volume and number of centers by year. surviving patients post lung transplantation. The striking feature remains that at 3 years of follow– up ⬎90% of patients have no limitation in activity.
HEART–LUNG TRANSPLANTATION The number of heart–lung transplantation procedures performed in pediatric patients continues on a downward trend, as shown in Figure 24. It appears
that fewer than 20 heart–lung transplants are performed annually as shown with the hatched bars. The solid line indicates the number of centers which also appears to be decreasing substantially, and there are now fewer than 10 centers reporting transplant activity in 1998. Figure 25 shows the indications for 135 children ages 1–10 for heart–lung transplantation. Congenital lung abnormalities, pri-
FIGURE 25 Pediatric heart–lung transplantation indications for recipients 1–10 years of age. Retx ⫽ re–transplantation.
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FIGURE 26 Pediatric heart–lung transplantation indications for recipients 11–17 years of age. Retx ⫽ re–transplantation.
mary pulmonary hypertension, and cystic fibrosis remain the three most common indications, and their percentages have remained relatively constant throughout the decade of observation. Figure 26 displays the same information for the adolescent age group, and it is apparent that the diagnosis of cystic
fibrosis has become the most common indication particularly in the last several years. The actuarial survival following heart–lung transplantation is shown in Figure 27. Almost 400 children have undergone heart–lung transplantation, and the overall patient survival half–life was 3.3 years. It is
FIGURE 27 Pediatric heart–lung transplantation actuarial survival (1982–1998).
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FIGURE 28 Pediatric heart–lung transplantation actuarial survival by era. apparent that the greatest risk of mortality is in the first year, and if one eliminates this high-risk period, the conditional half–life is extended to 7.6 years. The results seem more comparable to the results of isolated lung transplantation rather than isolated heart transplantation which indicates that lung function is
the predominant determinant of survival. Figure 28 shows the actuarial survival following lung transplantation as a function of era. Although the era effect is less striking than that seen for heart or lung transplantation alone, combined heart and lung transplantation patients have a significantly better survival in the most
FIGURE 29 Pediatric heart–lung transplant cause of death by time after transplantation.
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FIGURE 30 Pediatric heart–lung transplantation immunosuppression. recent era as compared to 1988 –1991. However, there was no significant difference between the most recent era and the middle period of 1992–1994. The cause of death as a function of time post transplant following heart–lung transplantation is shown in Figure 29. Like isolated lung transplantation, primary graft failure and
infection are the two most common causes of death in the first 30 days and throughout the first year. Following the first year chronic rejection and bronchiolitis obliterans become the major causes of mortality, with infection becoming less of a threat to patient survival. Figure 30 shows the immunosuppressive regimen
FIGURE 31 Functional status post pediatric heart–lung transplantation.
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TABLE X Post heart–lung transplantation (April 1994 –Dec. 1998) 1 Year Follow–up HTN Hyperlipidemia Diabetes Malignancy Renal Dysfunction
No Renal Dysfunction Renal Dysfunction Creatinine ⬎ 2.5 mg/dl Chronic Dialysis
following heart–lung transplantation for the subset of patients transplanted in the US between April 1994-December 1998. The use of tacrolimus has increased to now over 40% at 3 year follow– up. Virtually all patients remain on triple drug immunosuppression including anti–proliferative agents and prednisone. Figure 31 shows the functional status of heart– lung transplant recipients for the US subset of patients. The percent of patients who are rehabilitated is almost 80%, but remains less than that seen after either isolated lung or isolated heart transplantation. The percentage of rehabilitated patients is similar at both one and 3 year follow– up. The morbidity following heart–lung transplantation is shown on Table X which includes hypertension in about 40% at both 1 and 3 years and a concerning incidence of diabetes that increases from 12% at 1 year follow– up to 50% at 3 year follow– up. However, like heart and isolated lung transplantation, the renal function has remained excellent despite the broad spectrum immunosuppression.
CONCLUSION The Third Official Pediatric Report from the Registry of the International Society of Heart and Lung Transplantation extends the observations reported previously. An era effect has become evident for the first time, with improved survival in recent years most strikingly in heart transplantation but also in lung and heart–lung transplantation. The half–life following pediatric heart transplantation is now at 11.5 years with a conditional half–life at 14.4 years. The long–term survival is not as nearly as good following lung and heart–lung transplantation, with conditional survival remaining in the 6 –7 year range. Rehabilitation continues to be excellent for heart, lung, and heart–lung transplant recipients.
3 Year Follow–up % 36.0 4.0 12.5 4.0 95.8 0.0 0.0 4.2
No Renal Dysfunction Renal Dysfunction Creatinine ⬎ 2.5 mg/dl Chronic Dialysis
% 40.0 10.0 50.0 0.0 100.0 0.0 0.0 0.0
Rehospitalization is uncommon and morbidity is largely restricted to hypertension. There is an association between morbidity and the type of immunosuppressive regimen that is employed and as additional data is gathered on transplant recipients, we will further evaluate the relationship between immunosuppressive therapy, morbidity, and survival. The early post transplant period continues to be the highest risk time for all thoracic organ recipients. The increased hazard of early death after transplantation may be addressed by better organ availability and preservation, as well as by improved therapies for early graft rejection. The overall number of pediatric thoracic transplantations has remained stable. The number of centers has continued a downward trend, resulting in a concentration of experience at more active pediatric thoracic organ transplant centers. This Third Official Pediatric Report continues to expand our understanding of thoracic organ transplantation and enhances the sense of community among transplant professionals dealing with lethal thoracic disease in infancy, childhood, and adolescence. The report is only possible with the cooperation of the transplant centers providing timely, complete, and accurate data on their patients. The Registry staff and the transplant community are grateful for the contribution of each center and hope that these reports will continue to improve the quality of care for pediatric thoracic organ transplant recipients. REFERENCES 1. Boucek M, Novick R, Bennett L, Fiol B, Keck B, Hosenpud J. The Registry of the International Society of Heart and Lung Transplantation: Second Official Pediatric Report1998. J. Heart Lung Transplant 1998;17:1141– 60. 2. Hosenpud JD, Bennett L, Keck B, Fiol B, Boucek M, Novick R. The Registry of the International Society for Heart and Lung Transplantation: Sixteen Official Report-1999. J. Heart Lung Transplant 1999;18:611–26.
The Registry of the International Society of Heart and Lung Transplantation: Third Official Pediatric Report-1999 Mark M. Boucek, MD, Albert Faro, MD, Richard J. Novick, MD, Leah E. Bennett, PhD, Bennie Fiol, BS, Berkeley M. Keck, MPH, and Jeffrey D. Hosenpud, MD
T
he Third Pediatric Report of the Registry of the International Society of Heart and Lung Transplantation provides additional analyses of the experience during the first two decades of pediatric heart transplantation (1983 through 1998). The pediatric data are a subset of the entire Registry of thoracic transplantation but are important and biologically unique and can serve as a comparison to the overall experience. The patient population analyzed spans a period from the beginnings of pediatric heart transplantation in the early 1980’s. The current data indicates a recent trend toward improving survival. Further comparisons of patients with a congenital diagnosis leading to transplantation versus the diagnosis of cardiomyopathy provides a further insight into the risk of early mortality. The data also shows a relatively low annual risk of death in children transplanted under 10 years of age and followed for more than 3 years post heart transplantation. In this report, we continue the analysis of morbidity and its possible relation to immunosuppressive medications. Furthermore, for the first time, we have begun an analysis of the impact of thoracic organ trans-
From the International Society for Heart and Lung Transplantation, Dallas, Texas Submitted October 18, 1999; accepted October 22, 1999. Reprint requests: International Society for Heart and Lung Transplantation, 14673 Midway Road, Suite 108, Dallas, TX 75244 J Heart Lung Transplant 1999;18:1151–1172. Copyright © 1999 by the International Society for Heart and Lung Transplantation. 1053-2498/99/$–see front matter PII S1053-2498(99)00114-X
plantation on the critical pediatric outcome measure of growth.
DATA SET AND STATISTICAL METHODS The 1999 Pediatric Report contains world–wide data on 4,178 heart, 411 heart-lung, and 525 lung (single or double) transplantations performed through 1998. The data collection for the calendar year 1998 however is still being completed, and additional data will likely be presented in the next Pediatric Registry Report. The number of centers which have contributed to the data reported for the individual thoracic organ transplants include 208 heart, 65 heart–lung, 37 single lung, and 62 bilateral/ double lung transplantation centers. The univariate survival curve analysis and multivariate logistic regression methods were reported in the Second Official Pediatric Report.1
HEART TRANSPLANTATION The actual number of pediatric heart transplantations performed in 1997 was virtually identical to 1996. It is likely that for 1998, when data collection is completed, the number of transplants will be in the same range and continues a plateau phenomenon which began in the early 1990’s.1 The shaded bars in Figure 1 indicate the number of heart transplantations performed in the indicated year (Y1 axis), and the solid line indicates the number of centers reporting transplantations in each year (Y2 axis). In contrast to the plateau in the number of pediatric patients undergoing heart transplantation, the previously noted downward trend in the number 1151
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FIGURE 1 Pediatric heart transplantation volume and number of centers by year. of centers has continued with over a 20% reduction from the peak in 1994. A similar number of centers were reporting data in 1988 as in 1998. In comparison to the reduction in center numbers there was a 63% increase in the number of heart transplants performed between 1988 and 1998. These data
indicate a further concentration of the experience in pediatric heart transplantation and on average would represent the experience increasing from approximately 2.6 transplantations per center to 4.4 transplantations per center in 1998. Figures 2, 3, and 4 show the indications for heart transplantation.
FIGURE 2 Pediatric heart transplantation indications for recipients ⬍1 year of age. Retx ⫽ re–transplantation.
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FIGURE 3 Pediatric heart transplantation indications for recipients 1–10 years of age. Retx ⫽ re–transplantation.
These figures also include trend data for the two most common indications, myopathy and congenital heart disease in the lower panel. Figure 2 displays the indications for children ⬍1 year of age at the
time of transplant. Figure 3 represents children age 1–10 years, and Figure 4 for adolescents aged 11–17. There has been little change in the indications for transplantation over time. In the infant age group
FIGURE 4 Pediatric heart transplantation indications for recipients 11–17 years of age. Retx ⫽ re–transplantation.
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FIGURE 5 Pediatric heart transplantation actuarial survival (1982–1998). (⬍1 year), a diagnosis of congenital heart disease accounts for approximately 70% of the indications. In children age 1–10 years of age there is a relatively equal distribution between myopathy and congenital diagnosis whereas in the adolescent ages about 2⁄3 of the patients had myopathy and 1⁄3 had a congenital diagnosis. Interestingly, re–transplantation accounts for ⬍5% of all transplants in all ages. Figure 5 shows the actuarial survival for pediatric heart transplant recipients from 1982 through 1998. The conditional half-life for all pediatric heart transplant recipients is now ⬎14 years. The conditional (surviving the first year post transplant) half–life has increased 1.4 years since the 1998 Pediatric Report. In Figure 6 the actuarial survival for pediatric recipients is broken down into three eras for comparison. The era 1998 through 1991 is shown as triangles, the era 1992 through 1994 as open circles, and the era 1995 through 1998 as open squares. In the First Pediatric Registry Report there was no real era effect noted in the pediatric population through 1996. With the most recent data there is a significant improvement in survival in the most recent era. Coupling the overall expected conditional half–life with the recent improvement noted in the current era, decades long survival for pediatric heart transplant recipients seems likely. Still the number of patients at 13 years post transplant is relatively small. Additional longitudinal follow– up will provide a greater number of patients and more accuracy about long–term predictions. Figure 7 compares the
actuarial survival of pediatric recipients who underwent transplantation for the diagnosis of cardiomyopathy versus the age of the recipient. The largest number of patients are in the adolescent age group which mirrors the indications for transplantation of adolescents. There was no significant difference in the actuarial survival of patients transplanted for cardiomyopathy between the different age groups. On Figure 8 the actuarial survival for patients undergoing transplantation with the diagnosis of congenital heart disease is broken down by the age of the recipient. In contrast to the data shown for patients with cardiomyopathy, the largest number of patients is now in the ⬍1 year group which again reflects the indications for transplantation in this younger aged population. It is evident that there was an increased early mortality when the diagnosis leading to transplantation was congenital heart disease, which is most striking in the infant age group. There is a significant difference in mortality overall for the youngest recipients vs. the adolescent recipients noted primarily in the early post transplant time. However, by seven years the survival is virtually identical for all age ranges, which can be explained by the low decremental slope for the survival curve of infant age recipients. The risk factors by multivariate analysis for one year mortality after pediatric heart transplantation are shown in Table I.2 Repeat transplantation remains the variable with the highest risk for one year mortality followed by assist device support, ventila-
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FIGURE 6 Pediatric heart transplantation actuarial survival by era. tor support, and a diagnosis of congenital heart disease. As mentioned earlier transplantation during the most recent era is associated with a lower risk for one year mortality. The cause of death as a function of time in pediatric recipients following
heart transplantation is shown in Figure 9. In the early post transplant period, acute graft failure and cardiac failure remain the most common causes of death. During the first year acute rejection followed by infection are the two most common causes of
FIGURE 7 Pediatric heart transplantation actuarial survival (diagnosis of cardiomyopathy).
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FIGURE 8 Pediatric heart transplantation actuarial survival (diagnosis of congenital heart disease).
death. Between one and 3 years acute rejection followed by chronic rejection (which includes coronary artery disease) has become the two most common causes of death. When death occurs after 3 years, chronic rejection and coronary artery disease accounts for close to half of the late deaths with acute rejection still a persisting threat. Malignancy has remained an infrequent cause of death throughout all time periods including after 3 years. As noted in the previous Pediatric Registry Reports, there is still a large minority of patients whose cause of death does not fit into any frequently defined cate-
TABLE I Pediatric heart transplantation risk factors for 1 year mortality
Variable Repeat TX Balloon or VAD Ventilator Diagnosis ⫽ Congenital Heart Year of TX ⫽ 1995–1997 N ⫽ 3,199
Odds Ratio
P-value
95% Confidence Interval
2.11 1.99 1.56 1.44
0.004 0.003 0.0002 0.0002
1.28–3.50 1.27–3.12 1.24–1.97 1.19–1.75
0.68
0.0003
0.55–0.84
gory and is therefore categorized as “other”. These patients died largely from cerebrovascular accidents and nonspecific cardiovascular death. Nonspecific cardiovascular death may be in part explained by chronic rejection if more detailed data was available. The impact of rejection occurring during the first year post transplant on subsequent late survival is shown on Figure 10. The graph compares actuarial survival for two groups of patients (with or without rejection) who survived the first year. Patients with a history of rejection during the first year had a significantly greater mortality in subsequent years. Patients (shown in triangles) who were free from rejection and survived the first year had a significantly greater survival at 4 years, with a very flat curve indicating minimal yearly attrition. The data stops at 4 years in the free from rejection group since there are no other deaths as yet reported. We also looked at the risk of developing coronary artery disease late in patients surviving the first year according to the rejection experience during the first year. The data in Table II show that if rejection was present in the first year, there was a significantly higher risk of developing coronary artery disease at 2 year and 3 year follow– up (p ⬍ .05). Unfortunately, there is also a fairly large percentage of
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FIGURE 9 Pediatric heart cause of death. patients with incomplete data as shown in Table II. The largest unknown group were those in whom the rejection status was not specified. As seen in Figure 9, late mortality is most likely to be associated with chronic rejection/coronary artery
disease. The overall incidence of coronary artery disease is low; however, it should be noted that in pediatric patients the diagnosis is made predominantly with angiography which has been shown to under represent the true incidence of coronary
FIGURE 10 Heart transplantation actuarial survival versus rejection.
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TABLE II Post heart transplantation coronary artery disease (CAD) (US: April 1994 –Dec. 1998) Rejection in First Year
CAD ⴝ Unknown
CAD ⴝ No
CAD ⴝ Yes
CAD ⴝ Unknown
CAD ⴝ No
CAD ⴝ Yes
Yes No Unknown
30.3% (n ⫽ 86) 14.8% (n ⫽ 40) 55.9% (n ⫽ 447)
62.3% (n ⫽ 177) 82.6% (n ⫽ 223) 42.6% (n ⫽ 341)
7.4% (n ⫽ 21) 2.6% (n ⫽ 7) 1.5% (n ⫽ 12)
26.4% (n ⫽ 56) 9.3% (n ⫽ 13) 49.4% (n ⫽ 388)
66.0% (n ⫽ 140) 85.7% (n ⫽ 120) 47.6% (n ⫽ 374)
7.5% (n ⫽ 16) 5.0% (n ⫽ 7) 3.1% (n ⫽ 24)
2 Year Follow–up
3 Year Follow–up
artery disease. Overall when one looks at the cause of death in Figure 9, the impact of early rejection on late survival as shown in Figure 10, and finally the impact of early rejection on the subsequent development coronary artery disease as shown in Table II the importance of early graft rejection in subsequent patient survival is obvious. The maintenance immunosuppressive medications for pediatric recipients at the time of discharge, at one year and at 3 years post transplant are indicated on Figure 11. This year, for the first time, we have included data on mycophenolate mofetil (MMF). As reported previously all patents essentially receive a T– cell activation inhibitor with approximately 80% receiving cyclosporine at all time periods. The percent receiving tacrolimus has increased from the previous Report and is now greater than 20% at 3 years. Antiproliferative therapy in the form of azathioprine or MMF initially is used in virtually all patients, but by 3 years this number had been reduced to approximately 75%. The pediatric
population continues to provide a unique look at immunosuppressive therapy since by 3 years post transplant only 50% of patients remain on prednisone. This percent is reduced from approximately 75% at the time of transplant and less than 70% at one year. The pediatric population therefore provides an opportunity to evaluate the effect of prednisone use on survival and morbidity. As shown in Figure 11, 2⁄3 of the patients surviving to 1 year were on prednisone and 1⁄3 were off prednisone by 1 year. Figure 12 shows the actuarial survival curves for two groups of patients differentiated by whether or not they were still on prednisone at 1 year. Only patients surviving to 1 year were included in the analysis. The triangles represent those patients not on prednisone at 1 year and the open circles those on prednisone at 1 year. The curves are similar; however, the patients not on prednisone at 1 year had a significantly greater actuarial survival. This data does not evaluate subsequent prednisone use, and it is possible that there
FIGURE 11 Pediatric heart transplantation maintenance immunosuppression.
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FIGURE 12 Pediatric heart transplantation actuarial survival versus prednisone. was crossover between the two groups after the 1 year point in time. This data can only be interpreted as the affect of prednisone use in the first year and ideally cummulative prednisone dose should be evaluated. There may also be an adverse patient selection bias since patients at increased risk of rejection may have been left on or started on prednisone and thus may be expected to have a higher subsequent risk. As the cohort of patients (with more detailed data) transplanted between April 1994 and December 1998 grows, the inter– relation of factors such as rejection and prednisone use on outcomes will be looked at in future years in a multi–variate approach. A similar analysis of the use of prednisone in the first year, defined as patients still on prednisone at one year, on the subsequent development of coronary artery disease is shown in Table III. There was a significant (p ⬍ .05) increase in coronary artery disease for the group of patients still on prednisone
at 1 year. Like the analysis of rejection in the first year and the impact on subsequent coronary artery disease, there are a large number of patients where the data is incomplete. This data may reflect a selection process such that those patients still on prednisone at one year may represent a higher risk group for rejection, and therefore one would expect a higher risk of subsequent coronary artery disease. This data will be evaluated further in future reports. Table IV shows the most common morbidities following pediatric heart transplantation for the subset of US patients between April 1994 and December 1998 at 1 and 3 years post transplant. As has been reported in previous Pediatric Registry Reports, hypertension remains the most common diagnosis postoperatively. Approximately 40% of patients are categorized as being hypertensive. At 1 year 5% are reported to be hyperlipidemic, 3.2% diabetic, and 1.4% with a malignancy. These percentages increased slightly by the 3 year follow– up.
TABLE III Post heart transplantation coronary artery disease (CAD) (US: April 1994 –Dec. 1998) Prednisone in First Year
CAD ⴝ Unknown
CAD ⴝ No
CAD ⴝ Yes
CAD ⴝ Unknown
CAD ⴝ No
CAD ⴝ Yes
Yes No Unknown
32.2% (n ⫽ 241) 44.2% (n ⫽ 170) 73.6% (n ⫽ 162)
63.6% (n ⫽ 476) 54.5% (n ⫽ 210) 25.0% (n ⫽ 55)
4.3% (n ⫽ 32) 1.3% (n ⫽ 5) 1.4% (n ⫽ 3)
25.8% (n ⫽ 150) 30.9% (n ⫽ 97) 86.8% (n ⫽ 210)
67.7% (n ⫽ 394) 66.6% (n ⫽ 209) 12.8% (n ⫽ 31)
6.5% (n ⫽ 38) 2.5% (n ⫽ 8) 0.4% (n ⫽ 1)
2 Year Follow–up
3 Year Follow–up
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TABLE IV Post heart transplantation (April 1994 –Dec. 1998) 1 Year Followup HTN Hyperlipidemia Diabetes Malignancy Renal Dysfunction
No Renal Dysfunction
% 42.5 5.0 3.2 1.4 95.0
No Renal Dysfunction
% 36.8 9.4 2.7 2.0 95.7
Renal Dysfunction Creatinine ⬎ 2.5 mg/dl Chronic Dialysis
2.6 1.8 0.5
Renal Dysfunction Creatinine ⬎ 2.5 mg/dl Chronic Dialysis
3.3 1.0 0.0
Renal dysfunction, however, remains very uncommon with 95% of patients at 1 year and 3 years reporting no renal dysfunction. Table V displays an analysis of the presence or absence of hypertension according to the immunosuppressive medications for heart transplant recipients. There was a significant association between prednisone as a maintenance immunosuppressive agent and the presence of hypertension. There was no relationship between cyclosporine use and hypertension despite a significant relationship between tacrolimus and hypertension. This data is similar to the data shown in the Second Pediatric Registry Report. The quality of life of pediatric recipients can be reflected in their rehospitalization rate and functional status. Figure 13 shows that a slight majority of patients at one year follow– up have not required hospitalization since transplant. The most frequent indication for rehospitalization was rejection or infection. However, by 3 year follow– up 70% of patients were free from hospitalization during that year. Of those hospitalized, infection and rejection were nearly equal as the cause for readmission. Figure 14 shows the functional status for pediatric heart transplant recipients for the US subset be-
TABLE V Post heart transplantation drug treated hypertension (HTN) (April 1994 –Dec. 1998) % developing HTN by 3-year follow-up
Immunosuppression at 1 year Not on immuno. On immuno. p-value Cyclosporine Azathioprine Prednisone Tacrolimus
3 Year Followup
46.9% 28.6% 15.7% 33.3%
34.4% 37.6% 45.5% 54.8%
0.17 0.24 0.001 0.019
tween April 1994 and December 1998. More than 90% of patients were felt to have no activity limitation with only approximately 5% of patients requiring some form of assistance. In pediatric patients’ rehabilitation can also be assessed by growth parameters. Tables VI and VII show the height and weight for pediatric heart transplant recipients respectively. This data was for the US subgroup of patients transplanted between April 1, 1994 and December 31, 1997. They were broken down into four age groups: less than 1 year, 1–5 years, 6 –10 years, and 11–17 years, and only the data for the groups 1–5 years and 11–17 years were shown. The mean age, number of transplants with follow– up, and number with known height or weight parameters and the actual mean height and weight in centimeters or kilograms is displayed for the time at listing, pretransplant, 1 year follow– up, 2 year follow– up, and 3 year follow– up. A spurt in growth is evident in the year following transplant for all age groups except the adolescent age groups where there was no incremental increase in height parameters despite a mean age of 14.5 years at the time of listing. On average a growth of approximately 4 cm per year would have been expected for adolescents in this age range. In the younger age groups, the growth spurt following transplantation appeared to be sustained in subsequent years. The explanation for the lack of growth in adolescents following transplantation is uncertain. The 1999 report for pediatric heart transplantation is encouraging with an improving short term and long term actuarial survival, and other than hypertension, low morbidity and excellent rehabilitation. The analysis of mortality again indicates the important role of rejection. Rejection in the first year appears to be an indicator for subsequent events such as coronary artery disease and late mortality.
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FIGURE 13 Rehospitalization post pediatric heart transplantation.
LUNG TRANSPLANTATION The overall number of lung transplantations performed in pediatric patients has remained stable since 1995. Similar to heart transplantation there appears to be a reduction in the number of centers performing lung transplant procedures but with a
stabilization of the overall number of procedures performed. Figure 15 shows a graphic display of the number of lung transplants (vertical bars) by year with the solid line (Y2 axis) representing the number of centers. The indications for lung transplantation in the two youngest age groups are shown in Figure
FIGURE 14 Functional status post pediatric heart transplantation.
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TABLE VI Post heart transplantation: height statistics (Transplants: April 1994 –Dec. 1997)
Age group
1–5
11–17
Time point
Mean Age
N of Transplants/ follow-ups
N with known height
Mean (cm)
Std. Dev.
Listing Pre-transplant 1-year follow-up 2-year follow-up 3-year follow-up Listing Pre-transplant 1-year follow-up 2-year follow-up 3-year follow-up
2.77 2.97 4.07 5.10 6.03 14.45 14.72 15.70 16.50 17.65
226 226 165 138 96 311 311 258 212 137
194 175 156 88 50 291 272 165 101 37
87.3 88.3 95.1 105.1 109.1 158.1 159.1 159.4 159.8 159.2
14.2 14.0 12.2 13.0 13.7 15.8 15.4 14.0 13.4 13.7
16. In the infant age group congenital anomalies followed by chronic lung disease (CLD) are the two single most common indications but a large group of patients do not fit into any clear diagnostic category and are included in the other category. In the age group of 1–10 years cystic fibrosis makes an appearance as the most common single indication followed by primary pulmonary hypertension and interestingly retransplantation. Figure 17 shows the indications for the lung transplantation adolescent age group. In adolescents, cystic fibrosis is the most common indication for lung transplant, accounting for over 60% of patients. The indication for lung transplantation as a function of year of transplant is shown at the bottom of this Figure with cystic fibrosis represented by triangles, primary pulmonary hypertension as the solid squares, and idiopathic pulmonary fibrosis as the crossed points. Cystic fibrosis has accounted for the majority of lung
transplantations from 1993 onward and the percent has remained relatively stable. The actuarial survival of all pediatric lung transplant recipients from 1982–1998 is shown on Figure 18. A total of 486 patients are included in the Registry, and the survival half–life remains around 4.2 years which is comparable to that reported in the Second Pediatric Registry Report. The conditional half–life, which discounts for the high early mortality, was 6.8 years. By 6 years, post transplant there is about a 40% survival. Figure 19 breaks down the actuarial survival following lung transplantation for three periods of time. The 1988 –1991 data are shown in the triangles with the era 1992–1994 in the open circles and the era 1995–1998 as the open squares. There is a significant difference comparing survival in the most recent period from 1995–1998 to either of the earlier periods. This is the first time that we have documented an era effect on survival
TABLE VII Post heart transplantation: weight statistics (Transplants: April 1994 –Dec. 1997)
Age group
1–5
11–17
Time point
Mean Age
N of Transplants/ follow-ups
N with known weight
Mean (kg)
Std. Dev.
Listing Pre-transplant 1-year follow-up 2-year follow-up 3-year follow-up Listing Pre-transplant 1-year follow-up 2-year follow-up 3-year follow-up
2.77 2.97 4.07 5.10 6.03 14.45 14.72 15.70 16.50 17.65
226 226 165 138 96 311 311 258 212 137
211 187 127 92 55 294 279 185 111 45
11.9 12.1 16.2 18.1 19.5 51.4 51.6 60.4 60.5 62.0
4.2 3.9 5.4 6.4 6.3 18.5 17.9 21.0 20.4 19.3
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FIGURE 15 Pediatric lung transplantation volume and number of centers by year. after pediatric lung transplantation and is comparable to what has become evident in heart transplantation. The causes of death following lung transplantation are shown in Figure 20. The different pie diagrams represent the time post transplant. In the initial 30 days acute graft failure has remained the most common cause of death. Following the first
month, infection is the greatest risk to patient survival; in the period of 1–3 years and beyond chronic rejection/bronchiolitis becomes the dominant factor. Like the previous reports, it was clear that in the first year acute graft failure and infection were most likely to be the cause of death while later the sequelae of chronic rejection became the most common cause of mortality. Figure 21 shows the
FIGURE 16 Pediatric lung transplantation indications for recipients ⬍1 year of age and 1–10 years of age. Retx ⫽ re–transplantation.
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FIGURE 17 Pediatric lung transplantation indications for recipients 11–17 years of age. Retx ⫽ re–transplantation.
actuarial survival curves for the US subset of patients since 1984. Patients who survived the first year post transplant were evaluated in terms of their late survival according to whether they experienced acute rejection during the first year. The survival curve is normalized to 100% at 1 year. The subsequent curves show the patients free from rejection in the first year with triangles and those with rejection
in the first year shown as open circles. Within the subsequent years there is no significant difference in mortality for pediatric lung transplant recipients which is in contrast to heart transplant recipients. Figure 22 shows the immunosuppressive medications used following lung transplantation. This year, we have included the use of mycophenolate mofetil (MMF). Most patients remained on prednisone as
FIGURE 18 Pediatric lung transplantation actuarial survival (1982–1998).
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FIGURE 19 Pediatric lung transplantation actuarial survival by era. well as a T– cell activation inhibitor, either cyclosporin or tacrolimus, and an anti-proliferative agent in the form of MMF or azathioprine through year 3. The use of tacrolimus appears to have plateaued at around 20% which is comparable to the previous report. Table VIII shows the morbidity following
lung transplantation. Like after heart transplantation, hypertension is the most common form of morbidity, with an increase in incidence to 53% by 3 years. Diabetes was present in about 15% of patients at both 1 year and 3 years follow– up. Table IX shows the breakdown of patients with
FIGURE 20 Pediatric lung transplant cause of death by time after transplantation.
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FIGURE 21 Pediatric lung transplantation actuarial survival versus rejection. diabetes as a function of whether the indication for transplantation was cystic fibrosis or not. A large number of patients are lacking data on the presence or absence of diabetes. However, in those patients where diabetes was either reported as a positive finding or negative finding, there was a highly significant association with the diagnosis of cystic fibro-
sis at both 1 and 3 years follow– up. In the patients without cystic fibrosis only 1% were reported to have diabetes whereas in those patients with cystic fibrosis 21% were reported to have diabetes. Renal function has remained satisfactory with only 4% of patients reporting renal dysfunction at 3 years follow– up. Figure 23 shows the functional status of
FIGURE 22 Pediatric lung transplantation maintenance immunosuppression.
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TABLE VIII Post lung transplantation (April 1994 –Dec. 1998) 1 Year Follow–up HTN Hyperlipidemia Diabetes Malignancy Renal Dysfunction
3 Year Follow–up % 32.7 0.6 17.2 7.6 93.6 2.9 1.2 2.3
No Renal Dysfunction Renal Dysfunction Creatinine ⬎ 2.5 mg/dl Chronic Dialysis
% 53.2 0.0 14.9 2.1 93.6 4.3 2.1 0.0
No Renal Dysfunction Renal Dysfunction Creatinine ⬎ 2.5 mg/dl Chronic Dialysis
TABLE IX Post heart transplantation: Relationship of diabetes to diagnosis of cystic fibrosis (April 1994 –Dec. 1998) 1-year follow-up
3-year follow-up
Diabetes Status
Cystic Fibrosis ⴝ No
Cystic Fibrosis ⴝ Yes
Total
Cystic Fibrosis ⴝ No
Cystic Fibrosis ⴝ Yes
Total
Not Reported No Yes Total
120 (59.1%) 81 (39.9%) 2 (1.0%) 203 (100.0%)
42 (32.8%) 59 (46.1%) 27 (21.1%) 128 (100.0%)
162 (48.9%) 140 (42.3%) 29 (8.8%) 331 (100.0%)
18 (40.9%) 25 (56.8%) 1 (2.3%) 44 (100.0%)
1 (4.8%) 15 (71.4%) 6 (27.3%) 21 (100.0%)
19 (28.8%) 40 (60.6%) 7 (10.6%) 66 (100.0%)
Test of relationship between cystic fibrosis (No or Yes) and diabetes (No or Yes): at 1 year, p ⬍ 0.0001; at 3 years, p ⫽ 0.035
FIGURE 23 Functional status post pediatric lung transplantation.
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FIGURE 24 Pediatric heart–lung transplantation volume and number of centers by year. surviving patients post lung transplantation. The striking feature remains that at 3 years of follow– up ⬎90% of patients have no limitation in activity.
HEART–LUNG TRANSPLANTATION The number of heart–lung transplantation procedures performed in pediatric patients continues on a downward trend, as shown in Figure 24. It appears
that fewer than 20 heart–lung transplants are performed annually as shown with the hatched bars. The solid line indicates the number of centers which also appears to be decreasing substantially, and there are now fewer than 10 centers reporting transplant activity in 1998. Figure 25 shows the indications for 135 children ages 1–10 for heart–lung transplantation. Congenital lung abnormalities, pri-
FIGURE 25 Pediatric heart–lung transplantation indications for recipients 1–10 years of age. Retx ⫽ re–transplantation.
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FIGURE 26 Pediatric heart–lung transplantation indications for recipients 11–17 years of age. Retx ⫽ re–transplantation.
mary pulmonary hypertension, and cystic fibrosis remain the three most common indications, and their percentages have remained relatively constant throughout the decade of observation. Figure 26 displays the same information for the adolescent age group, and it is apparent that the diagnosis of cystic
fibrosis has become the most common indication particularly in the last several years. The actuarial survival following heart–lung transplantation is shown in Figure 27. Almost 400 children have undergone heart–lung transplantation, and the overall patient survival half–life was 3.3 years. It is
FIGURE 27 Pediatric heart–lung transplantation actuarial survival (1982–1998).
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FIGURE 28 Pediatric heart–lung transplantation actuarial survival by era. apparent that the greatest risk of mortality is in the first year, and if one eliminates this high-risk period, the conditional half–life is extended to 7.6 years. The results seem more comparable to the results of isolated lung transplantation rather than isolated heart transplantation which indicates that lung function is
the predominant determinant of survival. Figure 28 shows the actuarial survival following lung transplantation as a function of era. Although the era effect is less striking than that seen for heart or lung transplantation alone, combined heart and lung transplantation patients have a significantly better survival in the most
FIGURE 29 Pediatric heart–lung transplant cause of death by time after transplantation.
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FIGURE 30 Pediatric heart–lung transplantation immunosuppression. recent era as compared to 1988 –1991. However, there was no significant difference between the most recent era and the middle period of 1992–1994. The cause of death as a function of time post transplant following heart–lung transplantation is shown in Figure 29. Like isolated lung transplantation, primary graft failure and
infection are the two most common causes of death in the first 30 days and throughout the first year. Following the first year chronic rejection and bronchiolitis obliterans become the major causes of mortality, with infection becoming less of a threat to patient survival. Figure 30 shows the immunosuppressive regimen
FIGURE 31 Functional status post pediatric heart–lung transplantation.
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TABLE X Post heart–lung transplantation (April 1994 –Dec. 1998) 1 Year Follow–up HTN Hyperlipidemia Diabetes Malignancy Renal Dysfunction
No Renal Dysfunction Renal Dysfunction Creatinine ⬎ 2.5 mg/dl Chronic Dialysis
following heart–lung transplantation for the subset of patients transplanted in the US between April 1994-December 1998. The use of tacrolimus has increased to now over 40% at 3 year follow– up. Virtually all patients remain on triple drug immunosuppression including anti–proliferative agents and prednisone. Figure 31 shows the functional status of heart– lung transplant recipients for the US subset of patients. The percent of patients who are rehabilitated is almost 80%, but remains less than that seen after either isolated lung or isolated heart transplantation. The percentage of rehabilitated patients is similar at both one and 3 year follow– up. The morbidity following heart–lung transplantation is shown on Table X which includes hypertension in about 40% at both 1 and 3 years and a concerning incidence of diabetes that increases from 12% at 1 year follow– up to 50% at 3 year follow– up. However, like heart and isolated lung transplantation, the renal function has remained excellent despite the broad spectrum immunosuppression.
CONCLUSION The Third Official Pediatric Report from the Registry of the International Society of Heart and Lung Transplantation extends the observations reported previously. An era effect has become evident for the first time, with improved survival in recent years most strikingly in heart transplantation but also in lung and heart–lung transplantation. The half–life following pediatric heart transplantation is now at 11.5 years with a conditional half–life at 14.4 years. The long–term survival is not as nearly as good following lung and heart–lung transplantation, with conditional survival remaining in the 6 –7 year range. Rehabilitation continues to be excellent for heart, lung, and heart–lung transplant recipients.
3 Year Follow–up % 36.0 4.0 12.5 4.0 95.8 0.0 0.0 4.2
No Renal Dysfunction Renal Dysfunction Creatinine ⬎ 2.5 mg/dl Chronic Dialysis
% 40.0 10.0 50.0 0.0 100.0 0.0 0.0 0.0
Rehospitalization is uncommon and morbidity is largely restricted to hypertension. There is an association between morbidity and the type of immunosuppressive regimen that is employed and as additional data is gathered on transplant recipients, we will further evaluate the relationship between immunosuppressive therapy, morbidity, and survival. The early post transplant period continues to be the highest risk time for all thoracic organ recipients. The increased hazard of early death after transplantation may be addressed by better organ availability and preservation, as well as by improved therapies for early graft rejection. The overall number of pediatric thoracic transplantations has remained stable. The number of centers has continued a downward trend, resulting in a concentration of experience at more active pediatric thoracic organ transplant centers. This Third Official Pediatric Report continues to expand our understanding of thoracic organ transplantation and enhances the sense of community among transplant professionals dealing with lethal thoracic disease in infancy, childhood, and adolescence. The report is only possible with the cooperation of the transplant centers providing timely, complete, and accurate data on their patients. The Registry staff and the transplant community are grateful for the contribution of each center and hope that these reports will continue to improve the quality of care for pediatric thoracic organ transplant recipients. REFERENCES 1. Boucek M, Novick R, Bennett L, Fiol B, Keck B, Hosenpud J. The Registry of the International Society of Heart and Lung Transplantation: Second Official Pediatric Report1998. J. Heart Lung Transplant 1998;17:1141– 60. 2. Hosenpud JD, Bennett L, Keck B, Fiol B, Boucek M, Novick R. The Registry of the International Society for Heart and Lung Transplantation: Sixteen Official Report-1999. J. Heart Lung Transplant 1999;18:611–26.