| | Registry of the International Society for Heart and Lung Transplantation: Twenty-second Official Adult Lung and Heart-Lung Transplant Report—2005Received 28 April 2005; received in revised form 28 April 2005; accepted 24 May 2005.
Since its inception the Registry of the International Society for Heart and Lung Transplantation (ISHLT) has accrued data on 3,154 heart-lung recipients and 19,296 lung recipients, and it is a robust resource for the analysis of trends and outcomes. This section of the 22nd official report summarizes the current status of adult heart-lung and lung transplantation. Figures included in this report and additional slides that supplement this report can be accessed via the ISHLT’s website (http://www.ishlt.org).
Statistical methods  Survival rates were calculated by the Kaplan-Meier method and compared with the log-rank test; survival graphs were truncated when the remaining number of recipients was ≤10. Multivariate analyses were performed by Cox proportional hazards regression. The results of the multivariate analyses are reported as relative risks (RRs), with a corresponding p-value or 95% confidence limit. RR >1.0 indicates that the factor was associated with a higher probability of the event; conversely, RR <1.0 means the factor was linked to a lower likelihood of the event. Whenever appropriate, more detailed explanatory comments about the analytical methodology accompany the slides (in the Notes Page view), which are accessible from the website. Lung transplantation Centers and Activity The number of centers reporting lung transplantations each year is shown in Figure 1. Since 1997, the number of centers reporting lung transplantations has been relatively stable in the range of 108 to 114. The number of transplantations in 2003 decreased slightly from an all-time high of 1,767 in 2002. Nevertheless, an overall gradual growth in activity has continued since the rapid expansion of the earlier years subsided in 1996. The annual number of single-lung transplantations has been relatively constant since 1994, but the number of bilateral lung transplantations has been steadily increasing (Figure 2). In 2002, the number of bilateral lung transplantations surpassed the number of single-lung transplantations for the first time and, in 2003, the gap between the two procedures widened further. This trend toward bilateral transplantation is explored further in a subsequent section (see Indications and Operations). The distribution of lung transplantations by center volume is displayed in Figure 3 for the period January 1, 1998 to June 30, 2004. Among 146 centers that reported lung transplantations during this period, 83 (57%) averaged <10 transplantations per year, but these centers accounted for only 13% of all transplantations. The majority of transplantations (60%) were performed at 31 centers, which had an average annual activity of ≥20 transplantations per year. Donor and Recipient Profiles The mean age of lung donors increased over the last decade from 29.8 years in 1994 to 33.6 years in 2004, but has been relatively stable between 33 and 34 years since 1999. Although the average age of lung donors is still young, the proportion of older donors (age ≥50 years) doubled from 8.2% in 1994 to 17.4% in 2003. The age distribution of adult recipients has shifted as well (Figure 4). Since 1997, the proportion of recipients under 50 years of age has decreased. Meanwhile, the proportion of recipients ≥60 years of age has expanded noticeably, and this age group has comprised 20% of adult recipients since 1997. Indications and Operations The main pre-transplant indications for lung transplantation during the period January 1995 to June 2004 were chronic obstructive pulmonary disease (COPD, 38%), idiopathic pulmonary fibrosis (IPF, 17%), cystic fibrosis (CF, 17%) and α1-anti-trypsin deficiency emphysema (9%) (Table 1). The indications for lung transplantation are displayed by year in Figure 5, and no change in the distribution of diagnoses is apparent in recent years. | | |  | Diagnosis | SLT (N = 6,731) | BLT (N = 6,276) | Total (N = 13,007) | |
|---|
| COPD/emphysema | 3,541 (53%) | 1,462(23%) | 5,003(38%) | |
| Idiopathic pulmonary fibrosis | 1,618(24%) | 639(10.0%) | 2,257(17%) | |
| Cystic fibrosis | 151(2.2%) | 2,002(32%) | 2,153(17%) | |
| α1-anti-trypsin deficiency | 554(8.2%) | 571(9.1%) | 1,125(8.6%) | |
| Primary pulmonary hypertension | 79(1.2%) | 436(6.9%) | 515(4%) | |
| Sarcoidosis | 157(2.3%) | 166(2.6%) | 323(2.5%) | |
| Bronchiectasis | 45(0.7%) | 309(4.9%) | 354(2.7%) | |
| LAM | 55(0.8%) | 83(1.3%) | 138(1.1%) | |
| Congenital heart disease | 13(0.2%) | 118(1.9%) | 131(1.0%) | |
| Re-transplant: obliterative bronchiolitis | 74(1.1%) | 58(0.9%) | 132(1.0%) | |
| Obliterative bronchiolitis (not re-transplant) | 39(0.6%) | 80(1.3%) | 119(0.9%) | |
| Re-transplant: not obliterative bronchiolitis | 55(0.8%) | 46(0.7%) | 101(0.8%) | |
| Connective tissue disease | 34(0.5%) | 31(0.5%) | 65(0.5%) | |
| Histiocytosis X | 20(0.3%) | 19(0.3%) | 39(0.3%) | |
| Cancer | 7(0.1%) | 14(0.2%) | 21(0.2%) | |
| Other | 289(4.3%) | 242(3.8%) | 509(4.1%) | | | | |
During the last decade, the proportion of bilateral lung transplantations has increased for every major indication except CF (Figure 6), and in 2003 bilateral transplantation was the most common operation for α1-anti-trypsin deficiency emphysema, primary pulmonary hypertension (PPH) and, as expected, CF. Single-lung transplantation was still the leading operation for COPD and IPF, but bilateral transplantation has also been utilized increasingly for these diseases. Between 1993 and 2003, the share of bilateral transplantations more than doubled for both COPD (from 16% to 38%) and IPF (from 17% to 38%). The reasons for this move toward bilateral lung transplantation cannot be discerned from the Registry. The trend could have been motivated by better collective survival results after bilateral transplantation (see Survival section), by better lung function after bilateral transplantation to buffer complications, by institutional preferences and practices, or by other presently unknown factors. Immunosuppression A view of current immunosuppression practices was obtained from recipients transplanted between January 2000 and June 2003. Induction therapy was given to 38% to 46% of all recipients (Figure 7), and usage shifted away from the polyclonal anti-lymphocyte/anti-thymocyte globulins to the interleukin-2 receptor (IL-2R) antagonists. The impact of induction therapy on treatment for acute rejection in the first year after transplantation was also examined (Figure 8, Figure 9). Approximately 44% of recipients who did not receive induction were treated for acute rejection within their first post-transplantation year, and they experienced an average of almost 2 episodes of acute rejection per recipient during the first year. Induction therapy with the IL-2R antagonists did not substantially decrease the fraction of recipients who were treated for acute rejection, regardless of age range or gender. Although their effect was generally less potent than the polyclonal anti-lymphocyte/anti-thymocyte globulins, the IL-2R antagonists decreased the number of rejection episodes in the cohort as a whole, as well as in both genders, and in all age groups except the sub-set ≥65 years of age. (This decrease was statistically significant for the overall cohort and within females; however, although the decrease was of clinical interest, there was no statistically significant decrease within any of the age groups.) Thus, the IL-2R antagonists appeared to decrease the total burden of acute rejection (number of episodes) without increasing freedom from acute rejection (fraction of recipients treated for at least 1 episode of acute rejection). The polyclonal anti-lymphocyte/anti-thymocyte preparations significantly decreased both the portion of recipients who were treated for acute rejection and the average number of rejection episodes in the first year, and this effect was consistent across age and gender, with only 1 exception—there was no substantial reduction in the percentage of recipients treated for acute rejection in the 18- to 34-year age group. Although there was a decrease in the percentage of recipients treated for acute rejection in the ≥65-year age group, the reduction was not statistically significant. The reduction was statistically significant in all other age and gender groups. Medium-term survival, conditional on living for 2 weeks after transplantation, was not significantly affected by the use of induction therapy in 2 eras (April 1994 to June 2003: p = 0.084; January 2000 to June 2003: p = 0.236), and freedom from bronchiolitis obliterans syndrome (BOS) was not enhanced by induction therapy for follow-up in the decade spanning April 1994 to June 2004. A profile of maintenance drug usage at 1 and 5 years after transplantation was extracted from follow-up reports between January 2000 and June 2004 (Table 2). A calcineurin inhibitor plus a purine synthesis antagonist comprised the maintenance regime for approximately 75% of recipients at both 1 and 5 years after transplantation; no combination predominated, but tacrolimus plus mycophenolate mofetil was the most widely used regimen. The influence of maintenance regimens on treatment for acute rejection in the first year after transplantation is presented in Figure 10, Figure 11. Across age and gender, the combination of tacrolimus and mycophenolate mofetil was associated with the lowest percentage of recipients treated for acute rejection, and it was the regimen with the lowest overall average number of rejection episodes per recipient in the first year. Survival Kaplan-Meier survival for all lung transplant recipients from January 1994 through June 2003 is illustrated in Figure 12. Benchmark survival rates were 86% at 3 months, 76% at 1 year, 60% at 3 years, 49% at 5 years and 24% at 10 years. The mortality rate was highest in the first year, and there was slow attrition thereafter. Survival rates for single and bilateral transplant recipients were similar throughout the first year, but in subsequent years the survival rates gradually diverged. Both the half-life and the conditional half-life were significantly longer after bilateral than after single-lung transplantation. However, bilateral and single-lung recipients differed in many ways, such as in their age distribution and indications for transplantation, and these comparisons of survival have not been adjusted for other potentially influential variables. Thus, in the final analysis, the difference in survival might not be related solely to the procedure. Survival from 3 eras is compared in Figure 13. Survival rates have been significantly higher in the more recent eras (1995 to 1999, 2000 to June 2003) than in the earliest era (1988 to 1994). The improvement in survival was concentrated in the first 3 months after transplantation; beyond the first year, the downward slope in survival in the 3 eras is almost parallel. Thus, it appears that more effective strategies for conducting the operation and for preventing and treating early post-transplantation complications have evolved, whereas successful approaches for managing later problems such chronic rejection have not yet been developed. The effect of recipient age on survival is depicted in Figure 14. By 1 year after transplantation some stratification in survival among the age groups is noticeable, and subsequently the survival graphs diverge further. There was no significant difference in survival between the 18- to 34-year and the 35- to 49-year cohorts, but survival was significantly better than in these 2 younger age cohorts than in the 3 older age cohorts (50 to 59, 60 to 64, ≥65 years). The statistical comparisons among the age categories were not adjusted for other factors that could affect survival, and the differences among the groups may not be related simply to age. Nonetheless, because of the co-morbidities associated with increasing age and the deleterious effect of the post-transplantation regimen on some of these age-related conditions, an impact of age on long-term survival is not unexpected. Survival by pre-transplantation diagnosis is shown in Figure 15. The early separation in survival among the diagnoses is conspicuous, and it is probably related to differences in the complexity of the transplantation procedure among the underlying diseases. Thereafter, transplantation itself becomes the equalizer, and later mortality is primarily related to the complications of transplantation rather than the original diagnosis. For the most part, the initial survival strata among the diagnoses were sustained over the ensuing years. However, the relative position of COPD in the survival hierarchy shifted from the top at 1-year post-transplantation to near the bottom at 10 years after transplantation. Conditional survival neutralizes the disparities in early survival among the diagnoses, but the 1-year conditional survival rates also differ among the diagnoses (Figure 16). In this perspective, survival rates are divided into 2 clusters of diseases. Recipients with PPH, CF and α1-anti-trypsin deficiency emphysema had significantly better conditional survival out to 10 years after transplantation than those with COPD and IPF. The most obvious difference between these clusters is the younger age range of the recipients with PPH, CF and α1-anti-trypsin deficiency emphysema relative to the recipients with COPD and IPF, but other differences besides age and diagnosis could also have affected survival. Kaplan-Meier survival for bilateral and single-lung transplantations performed from January 1990 through June 2003 was compared for COPD, α1-anti-trypsin deficiency emphysema, IPF and PPH. Survival over 10 years after transplantation was significantly better after bilateral transplantation for COPD (p < 0.001) and for α1-anti-trypsin deficiency emphysema (p = 0.007); however, the comparisons were not adjusted for age or other potentially important factors. There was no significant difference in survival between single and bilateral transplantation for either PPH (p = 0.3) or IPF (p = 0.5). The impact of donor-recipient pre-transplantation cytomegalovirus (CMV) serologic status on survival was analyzed (Figure 17). Survival over the first 3 years after transplantation was significantly higher in CMV-seropositive recipients of transplants from CMV-seronegative donors than in any of the other donor-recipient CMV serologic pairings, including the presumably favorable combination of CMV-seronegative recipients with seronegative donors. Otherwise, no significant difference in survival was detected between other donor-recipient CMV serologic combinations. However, other variables were not controlled in this analysis, so the results could have been influenced by factors other than CMV status. Causes of Death and Risk Factors for Mortality The causes of death after lung transplantation are given in Table 3 for deaths occurring between January 1992 and June 2004. Graft failure and non-CMV infections were the principal fatal complications in the first 30 days, and these were major contributors to mortality in all subsequent time periods. Although acute rejection and CMV infection have been relatively common problems in the first year, neither has caused a large proportion of deaths. After the first year, approximately 27% of deaths have been attributed to bronchiolitis obliterans syndrome, and it remains the leading cause of late mortality. Moreover, some of the 15% to 17% of deaths in the graft failure category after the first year may have been related to chronic rejection. Malignancies and non-CMV infections were increasingly important contributors in recipients dying >1 year after transplantation. Risk factors for 1- and 5-year mortality were examined by multivariate logistic regression analysis. Categoric risk factors for 1-year mortality are presented in Table 4. Several continuous variables also had a significant impact, such as: donor and recipient age (Figure 18); recipient body mass index (BMI; Figure 19); donor weight (Figure 20); center volume (Figure 21); FEV1 (% predicted) in patients with IPF; recipient bilirubin; and recipient pulmonary vascular resistance. Categoric risk factors for 5-year mortality are summarized in Table 5. Continuous variables that significantly affected the risk of death include: recipient and donor age; recipient BMI and donor weight; and recipient pre-transplantation bilirubin, creatinine and pulmonary artery systolic pressure. Complications and Morbidities The most common morbidities among 1- and 5-year survivors are collated in Table 6 from follow-up reports between April 1994 and June 2003. Problems caused or aggravated by immunosuppressive drugs have been prevalent. Regardless of these morbidities, however, approximately 80% of 1-, 3-, 5- and 7-year survivors reported no activity limitation at follow-up. | | | | Outcome | Within 1 Year | Total number with known response | Within 5 years | Total number with known response | |
|---|
| Hypertension | 51.1% | (N = 6,994) | 85.9% | (N = 1,490) | |
| Renal dysfunction | | | | | |
| All | 25.7% | (N = 7,008) | 39.4% | (N = 1,596) | |
| Abnormal creatinine <2.5 mg/dl | 16.2% | | 22.7% | | |
| Creatinine >2.5 mg/dl | 7.6% | | 12.8% | | |
| Long-term dialysis | 1.9% | | 3.2% | | |
| Renal transplant | 0.0% | | 0.7% | | |
| Hyperlipidemia | 17.7% | (N = 7,362) | 46.8% | (N = 1,645) | |
| Diabetes | 21.5% | (N = 6,995) | 30.9% | (N = 1,467) | |
| Bronchiolitis obliterans | 8.8% | (N = 6,407) | 33.0% | (N = 1,178) | | | | |
Bronchiolitis obliterans syndrome (BOS) has been the most common chronic complication affecting the allograft itself. Aside from its contribution to mortality, it is the source of substantial morbidity among survivors. By 5 years after transplantation, 43% of recipients who survived at least 90 days after transplantation developed bronchiolitis obliterans syndrome (Figure 22). Although many recipients have succumbed to BOS or other complications by 5 years after transplantation, BOS has remained an ongoing problem in 33% of 5-year survivors (Table 6). Post-transplantation malignancies are listed in Table 7. Lymphoid neoplasms had the highest incidence among 1-year survivors, and skin cancers were the most common malignancy in 5- and 7-year survivors. By 5 years after transplantation, 17% of recipients had some type of cancer and, by 9 years, 30% developed a malignancy. Clinical Scenarios This new feature capitalizes on the predictive power of the Registry database to project expected survival in specific clinical scenarios. It is illustrated by one example here, and other examples are included in slides that are accessible via the website. The example (Figure 23) models a typical recipient with COPD undergoing bilateral lung transplantation with or without ventilator support at the time of the procedure. With all other relevant parameters being identical, the prejudicial effect of ventilator dependence at the time of transplantation on 1-year survival is very clear in this scenario. This type of modeling is a powerful application of the Registry that will be exploited more in the future. Heart-lung transplantation Centers and Activity The number of centers reporting heart-lung transplantations has decreased by approximately 40% since 1994 from a maximum of 63 to 37 in 2003 (Figure 1). Concomitantly, the decline in annual activity has continued, and only 74 heart-lung transplantations were recorded for 2003 (Figure 24). Only 5 centers reported ≥5 heart-lung transplantations per year for the period January 1, 1998 to June 30, 2004, and 65% of the transplantations were distributed among 76 different centers, which had activity at <5 heart-lung transplantations per year. However, >75% of the heart-lung transplantations were done at centers that performed ≥10 lung transplantations per year during this period. Indications PPH and pulmonary hypertension associated with Eisenmenger’s syndrome/congenital heart disease have been the main indications for heart-lung transplantation in adults (Table 8). Despite the widespread use of bilateral lung transplantation, CF has remained the third most common indication for heart-lung transplantation; however, the annual number of heart-lung transplantations for indications other than the pulmonary vascular diseases has been low (Figure 25). Immunosuppression Immunosuppression strategies for heart-lung transplantation have been similar to those for lung transplantation. From 2000 through 2003, the use of induction declined substantially, and therapy shifted away from the polyclonal anti-lymphocyte/anti-thymocyte globulins toward the IL-2R antagonists (Figure 26). A cross-sectional view of contemporary maintenance regimens was obtained from recipients who completed their 1- or 5-year follow-up between January 2001 and June 2004 (Figure 27). A calcineurin inhibitor plus a purine synthesis inhibitor was the conventional regimen, but other approaches were being employed in 20% of recipients at 1-year follow-up and 30% of recipients at 5-year follow-up. Although no pair of drugs predominated, tacrolimus with mycophenolate mofetil was the most frequently used combination; however, sirolimus (rapamycin) was a component in the maintenance regimen of 23% of recipients at 5-year follow-up. Prednisone-free protocols were rare; in the 1- and 5-year post-transplantation cohorts, only 2% and 4%, respectively, of the recipients were not receiving prednisone. Survival Kaplan-Meier survival is displayed in Figure 28. The early mortality rate has been very high, and survival rates were 71% at 3 months and 63% at 1 year. Thereafter, there has been a steady, gradual attrition, and the survival rates at 5 and 10 years were 43% and 28%, respectively. The overall survival half-life was 3.2 years; however, because mortality was concentrated in the first year, the conditional half-life was much higher at 9.0 years. Among the pulmonary vascular disorders, pre-transplantation diagnosis has been a major determinant of survival after heart-lung transplantation (Figure 29). Survival over 10 years has been similar for PPH and Eisenmenger’s syndrome, and survival for both of these has been superior to survival for other congenital anomalies. Causes of Death The causes of death after heart-lung transplantation are presented in Table 9. In the first 30 days, technical complications, graft failure and non-CMV infections accounted for 73% of the deaths; for the remainder of the first year, graft failure and non-CMV infections were the leading causes of death. Although both acute rejection and CMV infection have been common complications in the first year, mortality rates ascribed to these were low. Beyond the first year after transplantation, approximately 40% to 50% of deaths were attributed to bronchiolitis obliterans and lung graft failure; coronary artery vasculopathy and other cardiovascular complications were comparatively minor contributors to mortality. Complications and Morbidities The evolution of chronic rejection after heart-lung transplantation is shown in Figure 30. Coronary artery vasculopathy was overshadowed by bronchiolitis obliterans syndrome. By 5 years after transplantation, 43% of recipients with follow-up between April 1994 and June 2004 had bronchiolitis obliterans syndrome, whereas only 11% had coronary vasculopathy. Other post-transplantation morbidities among 1- and 5-year survivors are summarized in Table 10. Systemic hypertension that required drug therapy was the most widespread problem among survivors at 1 and 5 years after transplantation, but renal dysfunction, hyperlipidemia and diabetes mellitus were also prominent problems. Despite these morbidities, no activity limitation was reported for >85% of 1-, 3- and 5-year survivors with follow-up between April 1994 and June 2004. Post-transplantation malignancies are shown in Table 11. Lymphoid neoplasms had the highest incidence among 1-year survivors, but no specific malignancy was dominant among the 5-year survivors. By 5 years after transplantation, approximately 16% of recipients had developed some type of cancer. International Society for Heart and Lung Transplantation, Addison, Texas.  Reprint requests: Elbert P. Trulock, MD, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. Telephone: 314-454-8766. Fax: 314-454-5571.
PII: S1053-2498(05)00343-8 doi:10.1016/j.healun.2005.05.019 © 2005 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved. | |
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