http://www.jhltonline.org
The Registry of the International Society for Heart and Lung Transplantation: Seventeenth Official Pediatric Lung and Heart–Lung Transplantation Report—2014; Focus Theme: Retransplantation Christian Benden, MD, Samuel B. Goldfarb, MD, Leah B. Edwards, PhD, Anna Y. Kucheryavaya, MS, Jason D. Christie, MD, MS, Anne I. Dipchand, MD, FRCPC, Fabienne Dobbels, PhD, Bronwyn J. Levvey, RN, Lars H. Lund, MD, PhD, Bruno Meiser, MD, Roger D. Yusen, MD, MPH, and Josef Stehlik, MD, MPH; for the International Society for Heart and Lung Transplantation From the ISHLT Registry, Dallas, Texas.
This section of the 17th Official Registry Report of the International Society for Heart and Lung Transplantation (ISHLT) for 2014 summarizes data from pediatric lung transplant recipients and their donors for transplants that occurred through June 30, 2013. This report describes donor and recipient characteristics, transplant type, and recipient outcomes data. The full Registry slide set available online (www.ishlt.org/registries) provides more detail, additional analyses, and other information not included in this printed report. This Registry report focuses on an overall theme of retransplantation. This year’s update includes new retransplantation-related analyses, figures and tables. Data on heart–lung transplantation in children are not presented in this 2014 report, as the number of pediatric heart–lung transplant procedures remained very low. Data on pediatric heart–lung transplantation were presented in 2012.1 All slides associated with pediatric heart–lung transplantation are available online (www. ishlt.org/registries).
Reprint requests: Josef Stehlik, MD, MPH, Division of Cardiology, University of Utah Health Sciences Center, U.T.A.H. Cardiac Transplant Program, 50 N Medical Dr, 4A100 SOM, Salt Lake City, UT 84132. Telephone: 801-585-2340. Fax: 801-581-7735. E-mail address: [email protected] 1053-2498/$ - see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.healun.2014.08.005
Data collection and statistical methods Data are submitted to the ISHLT Registry by national and multinational organ/data exchange organizations, or by participating individual centers. Since its inception, 416 heart transplant centers, 241 lung transplant centers and 168 heart–lung transplant centers have reported data to the Registry. In our estimation, data submission to the Registry represents approximately two thirds of the thoracic transplant activity performed worldwide. This report used standard statistical methodology for analyses and reporting. Whenever appropriate, a more detailed explanation about the analytical methodology accompanied the website slides (in the “Notes Page” view of the website). To assess time-to-event rates (e.g., survival), this report employs the Kaplan–Meier method. Survival graphs (i.e., time-to-event graphs) underwent truncation when the number of analyzable individuals was o10. Within the era undergoing assessment, the analyses censored follow-up of the surviving recipients: (1) at the time last reported to be alive (e.g., most recent annual follow-up); or (2) at the time of retransplantation. Median time-to-event (e.g., survival) estimated the time-point at which 50% of all recipients experienced the event (e.g., death). Conditional analyses included only those patients who met the required criterion (e.g., survival past 1 year post-transplant). The log-rank test compared survival curves
1026
The Journal of Heart and Lung Transplantation, Vol 33, No 10, October 2014
Figure 1 Pediatric lung recipients. Recipient age distribution by year of transplant.
Figure 2 Pediatric lung transplants. Number of centers reporting transplants by location.
Figure 4 Pediatric lung transplants. Age distribution by location (transplants: January 2000 to June 2013).
Figure 5 Pediatric lung transplants. Donor age distribution (transplants: January 1986 to June 2013).
Figure 3 Pediatric lung transplants. Number of centers reporting transplants by pediatric center volume.
Figure 6 Pediatric lung transplants. Donor age distribution by location (transplants: January 2000 to June 2013).
among groups. To prevent spuriously statistically significant findings, we adjusted all pairwise tests for multiple comparisons (Scheffé or Bonferroni). For multivariable time-to-event analyses, this report used Cox proportional hazards regression. The analyses used the censoring approaches just described. Cox models only included transplant recipients who had data available for most of the risk factors in the final model. We used restricted cubic splines to fit continuous data variables. Model assumptions were tested and regression diagnostics were performed. The Cox models calculated hazard ratios (HRs) and corresponding p-values and 95% confidence intervals (CIs). An HR of 1 suggests that the presence of the factor (e.g.,
Figure 7 Pediatric lung transplants. Diagnosis distribution by location (transplants: January 2000 to June 2013).
Benden et al.
ISHLT 17th Pediatric Lung and Heart–Lung Report
donor gender) is not associated with the event (e.g., mortality). An HR 41.0 suggests that the presence of the factor is associated with a higher probability of the event studied (i.e., the group exposed to the factor has a higher hazard than the group not exposed), whereas an HR o1.0 suggests that the factor is associated with a lower probability of the event (i.e., the group exposed to the factor has a lower hazard than the group not exposed). A 95% CI of an HR that includes an HR of 1.0 does not show statistical significance for that factor as a risk factor for the outcome, whereas a 95% CI of an HR that does not include 1.0 shows statistical significance. Forest plots and tables show HR and 95% CI for categorical variables in the final models. Some analyses incorporated multiple imputation to estimate missing information for continuous data fields, such as ischemic time and donor age. This method produced an estimated value for the missing value based on the other characteristics of the patient, the donor and/or the transplant. Models fit on each imputed data set were combined to produce a final set of estimates and associated HR estimates and p-values. Registry data quality depends on center reporting accuracy and completeness. The Registry uses various quality control measures to ensure acceptable data quality and completeness before including the data in the main data set and using the data for analyses. Insufficient variable data completeness leads to variable exclusion from analyses. For deceased patients, some secondary outcomes may have been underreported in the final follow-up year before their death. The Registry did not capture the exact occurrence date for most secondary outcomes (e.g., renal dysfunction, bronchiolitis obliterans), but it did capture the window of occurrence (i.e., the event occurred between the first- and second-year annual follow-ups). For this report, which has retransplantation as its theme, a lung retransplant occurred when a lung or heart–lung transplant recipient received a subsequent lung transplant. For transplant recipients undergoing retransplantation, we ad-
Table 1
1027
dressed certain methodologic limitations. Retransplant events were identified by a prior transplant reported to the Registry. As identification of all transplants for an individual may not be complete, the number of retransplant events may be slightly underestimated. Regarding the primary diagnostic indication for transplantation, the investigators grouped diagnoses into broad categories to simplify data presentation. The online slide set provides more detailed diagnosis-specific analyses (see website).1 The Registry website provides Microsoft EXCEL spreadsheets that define and explain the data elements (e.g., individual diagnoses) used and others not used in this report. The investigators recommend cautious interpretation of unadjusted analyses and predictive/comparative risk models. For unadjusted analyses (e.g., survival curves stratified by gender), the different groups of interest may have an uneven distribution of clinical characteristics (e.g., recipient age, underlying diagnosis, comorbidities) and other factors (e.g., donor characteristics) associated with the outcome being assessed (e.g., survival). Models may have excluded variables that lacked statistical significance due to small sample size, and a Type II error may therefore have occurred (i.e., a significant association between the variable and the outcome may have escaped detection even though it existed). In addition, predictive models only included data captured in the Registry, and they did not adjust for all important known and unknown confounders. The models may lack generalizability for specific subgroups of patients or for specific settings (e.g., different organ allocation systems).
Volume, age distribution, indications and donor characteristics Since 1986, almost 2,000 pediatric lung transplants and almost 700 pediatric heart–lung transplants have been reported to the Registry. In 2012, the last complete year
Pediatric Lung Transplants: Indications by Age Group (Transplants: January 1990 to June 2013) o1 Year
1–5 Years
6–10 Years
11–17 Years
Diagnosis
n
%
n
%
n
%
n
%
Cystic fibrosis Idiopathic pulmonary arterial hypertension Retransplant, OB Congenital heart disease Idiopathic pulmonary fibrosis Obliterative bronchiolitis, not retransplant Retransplant, not OB Interstitial pneumonitis Pulmonary vascular disease Eisenmenger’s syndrome Pulmonary fibrosis, other Surfactant protein B deficiency COPD/emphysema Bronchopulmonary dysplasia Bronchiectasis Other
1 12 0 16 10 0 3 1 8 1 8 17 4 3 1 14
1.0 12.1
6 30 7 11 21 10 4 2 8 5 12 5 2 3 0 7
4.5 22.6 5.3 8.3 15.8 7.5 3.0 1.5 6.0 3.8 9.0 3.8 1.5 2.3
148 26 9 4 16 23 8 2 4 3 15 0 2 6 2 15
52.3 9.2 3.2 1.4 5.7 8.1 2.8 0.7 1.4 1.1 5.3
968 109 40 12 47 58 37 1 1 9 28 0 10 3 18 48
69.7 7.8 2.9 0.9 3.4 4.2 2.7 0.1 0.1 0.6 2.0
16.2 10.1 3.0 1.0 8.1 1.0 8.1 17.2 4.0 3.0 1.0 14.1
COPD, chronic obstructive pulmonary disease; OB, obliterative bronchiolitis.
5.3
0.7 2.1 0.7 5.3
0.7 0.2 1.3 3.5
1028
The Journal of Heart and Lung Transplantation, Vol 33, No 10, October 2014
Figure 8 Pediatric lung transplants. Induction immunosuppression (transplants: January 2001 to June 2013).
Figure 12 Lung transplants. Kaplan–Meier survival by recipient age group (transplants: January 1990 to June 2012).
Figure 9 Pediatric lung transplants. Kaplan–Meier survival stratified by induction use (transplants: January 2001 to June 2012).
Figure 13 Pediatric lung transplants. Kaplan–Meier survival by procedure type (transplants: January 1990 to June 2012).
Figure 10 Pediatric lung transplant recipients. Maintenance immunosuppression at time of follow-up (follow-ups: January 2001 to June 2013).
Figure 14 Pediatric lung transplants. Kaplan–Meier survival by diagnosis (transplants: January 1990 to June 2012).
Figure 11 Pediatric lung transplant recipients. Maintenance immunosuppression drug combinations at time of follow-up (follow-ups: January 2001 to June 2013).
Figure 15 Pediatric lung transplants. Kaplan–Meier survival by recipient age group (transplants: January 1990 to June 2012).
Benden et al.
ISHLT 17th Pediatric Lung and Heart–Lung Report
Figure 16 Pediatric lung transplants. Kaplan–Meier survival conditional to survival to 1 year after transplant by recipient age group (transplants: January 1990 to June 2012).
1029
Figure 19 Pediatric lung transplants. Functional status of surviving recipients (follow-ups: March 2005 to June 2013).
Table 2 Pediatric Lung Transplants: Cumulative Morbidity Rates in Survivors Within 1 Year Post-transplant (Follow-ups: April 1994 to June 2013)
Outcome
Figure 17 Pediatric lung transplants. Kaplan–Meier survival by era (transplants: January 1988 to June 2012).
Hypertension Renal dysfunction Abnormal creatinine r2.5 mg/dl Creatinine 42.5 mg/dl Chronic dialysis Renal transplant Hyperlipidemia Diabetes Bronchiolitis obliterans syndrome
Within 1 Year
Total number with known response
40.9% 9.4% 6.3%
727 756
2.0% 0.8% 0.3% 5.0% 22.2% 12.9%
746 757 700
Table 3 Pediatric Lung Transplants: Cumulative Morbidity Rates in Survivors Within 5 Years Post-transplant (Follow-ups: April 1994 to June 2013)
Outcome
Figure 18 Pediatric lung transplants. Kaplan–Meier survival by donor age for recipients age 11 to 17 years (transplants: January 1990 to June 2012).
included in this Registry report, the number of pediatric lung transplants was 93, compared with 106 in the previous year. The highest annual number of pediatric lung transplants ever reported to the Registry was 126 in 2010 (Figure 1). As in previous years, the majority of lung transplants were done in older children (11 to 17 years), with 77% of transplanted children being in this age group (Figure 1). Only 4 lung transplants were reported for recipients aged o1 year. The number of centers reporting pediatric lung transplants dropped from 43 in 2011 to 39 in 2012, with approximately half of centers located in Europe (N ¼ 20) and 15 centers in North America (Figure 2). As before, the vast majority of centers (N ¼ 34; 87%) undertook 1 to 4 procedures annually (Figure 3). For the first time in more
Hypertension Renal dysfunction Abnormal creatinine r2.5 mg/dl Creatinine 42.5 mg/dl Chronic dialysis Renal transplant Hyperlipidemia Diabetes Bronchiolitis obliterans syndrome
Within 5 years
Total number with known response
69.0% 31.3% 24.1%
210 224
4.5% 1.8% 0.9% 17.8% 35.7% 35.5%
214 224 172
than a decade, no center reported Z10 annual transplant procedures (Figure 3). The regional age distribution of pediatric lung transplants (Europe vs North America vs other) has remained unchanged with 84% of lung transplants in Europe performed in older children (Z11 years) compared with 68% in North America (Figure 4). Donor age distribution in pediatric lung transplants remains similar to findings in prior reports, with the majority
1030 Table 4
The Journal of Heart and Lung Transplantation, Vol 33, No 10, October 2014 Pediatric Lung Transplants: Cumulative Post-transplant Malignancy Rates in Survivors (Follow-ups: April 1994 to June 2013)
Malignancy/type
1-year survivors
5-year survivors
7-year survivors
No malignancy Malignancy (all types combined) Malignancy typea Lymphoma Other Type not reported
729 (94.7%) 41 (5.3%)
208 (89.3%) 25 (10.7%)
118 (90.8%) 12 (9.2%)
38 2 1
25 1 0
12 0 0
a Recipients may have had more than one type of malignancy, so the sum of individual malignancy types may be greater than total number with malignancy.
Table 5
Pediatric Lung Transplant Recipients (January 1995 to June 2012): Risk Factors for 1-Year Mortality/Graft Failure (N ¼ 852)
Variable
Number
Hazard ratio
p-value
95% confidence interval
On ventilator Diagnosis ¼ retransplanta Year of transplant: 1995 to 2002 vs 2003 to June 2012 Donor CMVþ/Recipient CMV Recipient age
147 58 354 270
2.64 2.42 1.66 1.49
o0.0001 0.0017 0.0035 0.0147 0.0210
1.72–4.07 1.39–4.19 1.18–2.34 1.08–2.05
a
Retransplant includes those with a retransplant diagnosis or a previous transplant was reported. Reference group ¼ cystic fibrosis.
Table 6
Pediatric Lung Transplant Recipients (January 1995 to June 2008): Risk Factors for 5-Year Mortality/Graft Failure (N ¼ 646)
Variable
Number
Hazard ratio
p-value
95% confidence interval
On ventilator Year of transplant: 1995 to 2001 vs 2002 to June 2008 Recipient age Pediatric transplant center volume
104 312
1.73 1.33
0.0021 0.0137 0.0095 0.0051
1.22–2.45 1.06–1.67
Table 7
Pediatric Lung Recipients: Cause of Death (Deaths: January 1992 to June 2013)
Cause of death
0–30 days (N ¼ 126)
31 days to 1 year (N ¼ 182)
41 year to 3 years (N ¼ 234)
43 years to 5 years (N ¼ 112)
45 years (N ¼ 115)
Bronchiolitis Acute rejection Lymphoma Malignancy, non-lymphoma CMV Infection, non-CMV Graft failure Cardiovascular Technical Multiple-organ failure Other
0 3 0 0 0 17 35 21 15 13 22
18 4 8 2 6 59 33 8 5 22 17
87 3 7 1 0 35 59 4 6 11 21
42 3 4 0 0 20 26 1 3 4 9
(37.5%) (2.7%) (3.6%)
55 (47.8%) 0 5 (4.3%) 5 (4.3%)
(17.9%) (23.2%) (0.9%) (2.7%) (3.6%) (8.0%)
10 22 1 2 6 9
(2.4%)
(13.5%) (27.8%) (16.7%) (11.9%) (10.3%) (17.5%)
(9.9%) (2.2%) (4.4%) (1.1%) (3.3%) (32.4%) (18.1%) (4.4%) (2.7%) (12.1%) (9.3%)
(37.2%) (1.3%) (3.0%) (0.4%) (15.0%) (25.2%) (1.7%) (2.6%) (4.7%) (9.0%)
(8.7%) (19.1%) (0.9%) (1.7%) (5.2%) (7.8%)
CMV, cytomegalovirus.
(63%) of donors o18 years of age (Figure 5). Identical to last year’s report, 6% of donors were 50 to 59 years of age and o1% were Z60 years of age (Figure 5). As reported in 2013, donor age distribution varied considerably between regions: in North America, the majority of donors used were pediatric (74%), whereas, in Europe, less than half of the donors (42%) were o18 years of age (Figure 6). There have been some changes with regard to the diagnoses leading to lung transplantation in children over
the last 2 decades, but the vast majority of transplant procedures are still carried out in children with end-stage cystic fibrosis (CF) lung disease, and there remain considerable regional differences. In North America, just over half of the pediatric lung transplant recipients had CF compared with 71% in Europe (Figure 7). Further, the distribution of underlying diagnoses in pediatric lung transplant recipients depends on the age group. In children Z11 years of age, 70% were transplanted for CF, compared with 52% in younger
Benden et al.
ISHLT 17th Pediatric Lung and Heart–Lung Report
Figure 20 Pediatric lung transplants. Freedom from bronchiolitis obliterans syndrome (follow-ups: April 1994 to June 2013).
Figure 21 Pediatric lung transplants. Freedom from bronchiolitis obliterans syndrome by age group (follow-ups: April 1994 to June 2013).
Figure 22 Pediatric lung recipients. Freedom from bronchiolitis obliterans syndrome by diagnosis (follow-ups: April 1994 to June 2013).
1031
Figure 24 Pediatric lung transplants. Kaplan–Meier survival by transplant type (transplants: January 1994 to June 2012).
Figure 25 Pediatric lung transplants. Survival by transplant type and inter-transplant interval (transplants: January 1988 to June 2012).
Figure 26 Pediatric lung retransplants. Survival by diagnosis (retransplants: January 1988 to June 2012).
children 6 to 10 years of age (Table 1). In recipients o1 year of age, surfactant protein B deficiency, congenital heart disease and idiopathic pulmonary arterial hypertension were the 3 most frequent diagnoses leading to lung transplantation, respectively (Table 1).
Immunosuppressive therapy Induction Figure 23 Pediatric lung retransplants (retransplants: January 1994 to June 2013).
Compared with the previous year, there is no change regarding the use of induction immunosuppression in
1032
The Journal of Heart and Lung Transplantation, Vol 33, No 10, October 2014
pediatric lung transplantation. The majority of children (62%) received induction treatment, generally with an interleukin-2 (IL-2) receptor antagonist (48% of all patients) (Figure 8). As previously described,2 there was no significant survival difference seen when recipients were stratified by induction use (Figure 9).
Maintenance A triple maintenance immunosuppressive treatment, including a calcineurin inhibitor (CNI), mycophenolate mofetil/mycophenolic acid (MMF/MPA) and prednisone, was the most common maintenance immunosuppression regimen for children after lung transplantation (Figures 10 and 11). Tacrolimus was the most commonly prescribed CNI in children in the first year after transplant (84% of cases) (Figure 10). MMF/ MPA was the first choice of cell-cycle inhibitor, used in almost 70% of cases at 1 year after transplantation, with 62% receiving it in combination with tacrolimus (Figures 10 and 11). Even at 5-year follow-up, half the children were on tacrolimus plus MMF/MPA as maintenance therapy (Figure 11). The number of pediatric recipients on a combination of tacrolimus plus sirolimus/everolimus at 5 years post-transplant has reached 8% (Figure 11). Similar to the previous year’s report,2 490% of children received prednisone at 5 years post-transplant (Figure 10).
Outcomes of primary transplants Survival in children after lung transplantation is similar to that reported in adults with a median survival of 5.1 vs 5.6 years, respectively, for patients transplanted between January 1990 and June 2012 (Figure 12). Survival after bilateral/double pediatric lung transplantation (N ¼ 1,654) is better than that after single lung transplantation (N ¼ 94), with a median survival of 5.5 vs 1.9 years, respectively (Figure 13). No statistical difference in survival was seen between recipients transplanted for CF compared with those transplanted for non-CF diagnoses (Figure 14). Although the comparison is not statistically significant, overall and 1-year conditional survival rates in children Z11 years of age were numerically lower compared with younger transplant recipients (Figures 15 and 16). Survival of pediatric lung recipients in the 2 most recent eras (2000 to 2005 and 2006 to June 2012) was superior to the previous era of 1988 to 1999, but there was no significant difference in survival between the 2 most recent eras 2000 to 2005 and 2006 to June 2012) (Figure 17). Survival of recipients 11 to 17 years old at the time of transplant stratified by donor age is shown in Figure 18. Although no pairwise comparisons were statistically significant, there was a numerical trend for worse survival in the group of pediatric recipients who received lungs from older donors.
physician, with 480% of surviving children followed-up between 2005 and 2013 having a functional status of Z80% for Lansky score through 3 years post-transplant (Figure 19).
Complications and morbidities At 1-year post-transplant, hypertension was the most common morbidity in 440% of surviving children, followed by diabetes mellitus (22%) and bronchiolitis obliterans syndrome (BOS) (13%) (Table 2). More than two thirds of children within 5 years post-transplant (followups: April 1994 to June 2013) were reported to have hypertension (Table 3). Diabetes mellitus (36%), BOS (35%) and chronic renal impairment (31%) were also frequent morbidities within 5 years post-transplant (Table 3). Further details of the cumulative prevalence of morbidities are presented in Tables 2 and 3. At 5 years posttransplant, 11% of surviving transplant recipients were diagnosed with a malignancy, and almost all malignancies were lymphomas (Table 4). Significant risk factors for 1-year mortality or graft failure were pre-transplant ventilator use, retransplantation, earlier transplantation era, cytomegalovirus (CMV), high-risk donor/recipient mismatch (Table 5) and older recipient age (Table 6).
Bronchiolitis obliterans syndrome BOS, the most common form of chronic lung allograft dysfunction, remains the most frequent overall cause of morbidity, with a prevalence of 450% in surviving transplant recipients by 5 years post-transplant (Figure 20). There was a trend for higher cumulative incidence of BOS in children transplanted at Z11 years of age compared with younger recipients. Almost 60% of recipients transplanted at age Z11 years had BOS by 5 years post-transplant (Figure 21). There was also a trend for lower freedom from BOS in surviving CF recipients compared with recipients transplanted for idiopathic pulmonary arterial hypertension (IPAH)—45% vs 57% at 5 years post-transplant, respectively (Figure 22).
Cause of death The most common cause of death early after transplantation (within the first 30 days) remains graft failure, occurring in 28% of cases (Table 7). Up to 1 year after transplantation, non-CMV infection was the leading cause of death, occurring in 32% of recipients. Beyond the first year posttransplant, BOS has remained, by far, the primary cause of death (deaths: January 1992 to June 2013), with this figure increasing from 37% between 1 and 5 years post-transplant to 48% of deaths at 45 years post-transplant (Table 7).
Functional status
Retransplantation
Overall functional status of children after lung transplantation remained good, as reported by the
This report has focused on an overall theme of retransplantation. In almost 2 decades (January 1994 to June 2013),
Benden et al.
ISHLT 17th Pediatric Lung and Heart–Lung Report
a total of only 106 retransplants were reported in pediatric lung transplant recipients (Figure 23). The vast majority of retransplants were performed beyond 1 year after the primary transplant procedure (Figure 23). In approximately half of these cases, retransplants were undertaken for obliterative bronchiolitis. Between January 1990 and June 2013, 77% of retransplants were carried out in patients 11 to 17 years of age. In recipients with obliterative bronchiolitis, 71% (40 of 56) of retransplants were done in recipients Z11 years old (Table 1), similar to figures in recipients with indications other than obliterative bronchiolitis—60 of 75 (80%) recipients Z11 years old (note: Table 1 does not identify all retransplants with other indications). Retransplant as the diagnosis leading to lung transplantation in children was slightly less common in Europe (4% of all transplants) compared with North America (7% of all transplants carried out between January 2000 and June 2013 (Figure 7). Survival after retransplantation (N ¼ 116) was significantly inferior compared with all primary lung transplant procedures (N ¼ 1,490) performed from January 1994 to June 2012 (Figure 24). In this period, 1- and 5-year survival rates for patients after primary transplant were 82% and 52%, respectively, compared with 57% and 33%, respectively, for patients after retransplantation (Figure 24). Survival after retransplantation remained significantly inferior compared with primary transplants, even if retransplant procedures were stratified by inter-transplant interval (Figure 25). Although the difference did not reach statistical significance, perhaps due to the small number of patients and events, 1-year survival for retransplants undertaken o1 year after the primary transplant (N ¼ 34) was half that of retransplants done Z1 year after the primary transplant (N ¼ 82)—32% and 61%, respectively (Figure 25). The analyses were limited to patients o18 years of age at time
1033
of retransplant, and included deceased as well as living donors. Survival after retransplant was not significantly different if stratified by diagnosis (obliterative bronchiolitis, N ¼ 60, vs non-obliterative bronchiolitis, N ¼ 66) (Figure 26). In conclusion, this 2014 ISHLT Registry report on pediatric lung transplantation shows favorable survival in children undergoing lung transplantation as the ultimate therapy for end-stage lung diseases, with results of lung transplantation in children comparable to those seen in adult recipients. To date, however, BOS continues to be the greatest obstacle to improved long-term outcomes across all age groups. Retransplantation remains the last therapy option, generally for patients with progressive BOS, as acceptable outcomes after retransplantation seem achievable only in highly selected candidates. Thus, the number of pediatric lung retransplant procedures reported to the Registry has remained low.
Disclosure statement All relevant disclosures for the Registry Director, Executive Committee Members and authors are on file with the ISHLT and can be made available for review by contacting the Executive Director of the ISHLT.
References 1. Benden C, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Fifteenth Pediatric Lung and Heart–Lung Transplantation Report—2012. J Heart Lung Transplant 2012;31:1087-95. 2. Benden C, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Sixteenth Official Pediatric Lung and Heart–Lung Transplantation Report—2013. J Heart Lung Transplant 2013;32:989-97.
The Registry of the International Society for Heart and Lung Transplantation: Seventeenth Official Pediatric Lung and Heart–Lung Transplantation Report—2014; Focus Theme: Retransplantation Christian Benden, MD, Samuel B. Goldfarb, MD, Leah B. Edwards, PhD, Anna Y. Kucheryavaya, MS, Jason D. Christie, MD, MS, Anne I. Dipchand, MD, FRCPC, Fabienne Dobbels, PhD, Bronwyn J. Levvey, RN, Lars H. Lund, MD, PhD, Bruno Meiser, MD, Roger D. Yusen, MD, MPH, and Josef Stehlik, MD, MPH; for the International Society for Heart and Lung Transplantation From the ISHLT Registry, Dallas, Texas.
This section of the 17th Official Registry Report of the International Society for Heart and Lung Transplantation (ISHLT) for 2014 summarizes data from pediatric lung transplant recipients and their donors for transplants that occurred through June 30, 2013. This report describes donor and recipient characteristics, transplant type, and recipient outcomes data. The full Registry slide set available online (www.ishlt.org/registries) provides more detail, additional analyses, and other information not included in this printed report. This Registry report focuses on an overall theme of retransplantation. This year’s update includes new retransplantation-related analyses, figures and tables. Data on heart–lung transplantation in children are not presented in this 2014 report, as the number of pediatric heart–lung transplant procedures remained very low. Data on pediatric heart–lung transplantation were presented in 2012.1 All slides associated with pediatric heart–lung transplantation are available online (www. ishlt.org/registries).
Reprint requests: Josef Stehlik, MD, MPH, Division of Cardiology, University of Utah Health Sciences Center, U.T.A.H. Cardiac Transplant Program, 50 N Medical Dr, 4A100 SOM, Salt Lake City, UT 84132. Telephone: 801-585-2340. Fax: 801-581-7735. E-mail address: [email protected] 1053-2498/$ - see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.healun.2014.08.005
Data collection and statistical methods Data are submitted to the ISHLT Registry by national and multinational organ/data exchange organizations, or by participating individual centers. Since its inception, 416 heart transplant centers, 241 lung transplant centers and 168 heart–lung transplant centers have reported data to the Registry. In our estimation, data submission to the Registry represents approximately two thirds of the thoracic transplant activity performed worldwide. This report used standard statistical methodology for analyses and reporting. Whenever appropriate, a more detailed explanation about the analytical methodology accompanied the website slides (in the “Notes Page” view of the website). To assess time-to-event rates (e.g., survival), this report employs the Kaplan–Meier method. Survival graphs (i.e., time-to-event graphs) underwent truncation when the number of analyzable individuals was o10. Within the era undergoing assessment, the analyses censored follow-up of the surviving recipients: (1) at the time last reported to be alive (e.g., most recent annual follow-up); or (2) at the time of retransplantation. Median time-to-event (e.g., survival) estimated the time-point at which 50% of all recipients experienced the event (e.g., death). Conditional analyses included only those patients who met the required criterion (e.g., survival past 1 year post-transplant). The log-rank test compared survival curves
1026
The Journal of Heart and Lung Transplantation, Vol 33, No 10, October 2014
Figure 1 Pediatric lung recipients. Recipient age distribution by year of transplant.
Figure 2 Pediatric lung transplants. Number of centers reporting transplants by location.
Figure 4 Pediatric lung transplants. Age distribution by location (transplants: January 2000 to June 2013).
Figure 5 Pediatric lung transplants. Donor age distribution (transplants: January 1986 to June 2013).
Figure 3 Pediatric lung transplants. Number of centers reporting transplants by pediatric center volume.
Figure 6 Pediatric lung transplants. Donor age distribution by location (transplants: January 2000 to June 2013).
among groups. To prevent spuriously statistically significant findings, we adjusted all pairwise tests for multiple comparisons (Scheffé or Bonferroni). For multivariable time-to-event analyses, this report used Cox proportional hazards regression. The analyses used the censoring approaches just described. Cox models only included transplant recipients who had data available for most of the risk factors in the final model. We used restricted cubic splines to fit continuous data variables. Model assumptions were tested and regression diagnostics were performed. The Cox models calculated hazard ratios (HRs) and corresponding p-values and 95% confidence intervals (CIs). An HR of 1 suggests that the presence of the factor (e.g.,
Figure 7 Pediatric lung transplants. Diagnosis distribution by location (transplants: January 2000 to June 2013).
Benden et al.
ISHLT 17th Pediatric Lung and Heart–Lung Report
donor gender) is not associated with the event (e.g., mortality). An HR 41.0 suggests that the presence of the factor is associated with a higher probability of the event studied (i.e., the group exposed to the factor has a higher hazard than the group not exposed), whereas an HR o1.0 suggests that the factor is associated with a lower probability of the event (i.e., the group exposed to the factor has a lower hazard than the group not exposed). A 95% CI of an HR that includes an HR of 1.0 does not show statistical significance for that factor as a risk factor for the outcome, whereas a 95% CI of an HR that does not include 1.0 shows statistical significance. Forest plots and tables show HR and 95% CI for categorical variables in the final models. Some analyses incorporated multiple imputation to estimate missing information for continuous data fields, such as ischemic time and donor age. This method produced an estimated value for the missing value based on the other characteristics of the patient, the donor and/or the transplant. Models fit on each imputed data set were combined to produce a final set of estimates and associated HR estimates and p-values. Registry data quality depends on center reporting accuracy and completeness. The Registry uses various quality control measures to ensure acceptable data quality and completeness before including the data in the main data set and using the data for analyses. Insufficient variable data completeness leads to variable exclusion from analyses. For deceased patients, some secondary outcomes may have been underreported in the final follow-up year before their death. The Registry did not capture the exact occurrence date for most secondary outcomes (e.g., renal dysfunction, bronchiolitis obliterans), but it did capture the window of occurrence (i.e., the event occurred between the first- and second-year annual follow-ups). For this report, which has retransplantation as its theme, a lung retransplant occurred when a lung or heart–lung transplant recipient received a subsequent lung transplant. For transplant recipients undergoing retransplantation, we ad-
Table 1
1027
dressed certain methodologic limitations. Retransplant events were identified by a prior transplant reported to the Registry. As identification of all transplants for an individual may not be complete, the number of retransplant events may be slightly underestimated. Regarding the primary diagnostic indication for transplantation, the investigators grouped diagnoses into broad categories to simplify data presentation. The online slide set provides more detailed diagnosis-specific analyses (see website).1 The Registry website provides Microsoft EXCEL spreadsheets that define and explain the data elements (e.g., individual diagnoses) used and others not used in this report. The investigators recommend cautious interpretation of unadjusted analyses and predictive/comparative risk models. For unadjusted analyses (e.g., survival curves stratified by gender), the different groups of interest may have an uneven distribution of clinical characteristics (e.g., recipient age, underlying diagnosis, comorbidities) and other factors (e.g., donor characteristics) associated with the outcome being assessed (e.g., survival). Models may have excluded variables that lacked statistical significance due to small sample size, and a Type II error may therefore have occurred (i.e., a significant association between the variable and the outcome may have escaped detection even though it existed). In addition, predictive models only included data captured in the Registry, and they did not adjust for all important known and unknown confounders. The models may lack generalizability for specific subgroups of patients or for specific settings (e.g., different organ allocation systems).
Volume, age distribution, indications and donor characteristics Since 1986, almost 2,000 pediatric lung transplants and almost 700 pediatric heart–lung transplants have been reported to the Registry. In 2012, the last complete year
Pediatric Lung Transplants: Indications by Age Group (Transplants: January 1990 to June 2013) o1 Year
1–5 Years
6–10 Years
11–17 Years
Diagnosis
n
%
n
%
n
%
n
%
Cystic fibrosis Idiopathic pulmonary arterial hypertension Retransplant, OB Congenital heart disease Idiopathic pulmonary fibrosis Obliterative bronchiolitis, not retransplant Retransplant, not OB Interstitial pneumonitis Pulmonary vascular disease Eisenmenger’s syndrome Pulmonary fibrosis, other Surfactant protein B deficiency COPD/emphysema Bronchopulmonary dysplasia Bronchiectasis Other
1 12 0 16 10 0 3 1 8 1 8 17 4 3 1 14
1.0 12.1
6 30 7 11 21 10 4 2 8 5 12 5 2 3 0 7
4.5 22.6 5.3 8.3 15.8 7.5 3.0 1.5 6.0 3.8 9.0 3.8 1.5 2.3
148 26 9 4 16 23 8 2 4 3 15 0 2 6 2 15
52.3 9.2 3.2 1.4 5.7 8.1 2.8 0.7 1.4 1.1 5.3
968 109 40 12 47 58 37 1 1 9 28 0 10 3 18 48
69.7 7.8 2.9 0.9 3.4 4.2 2.7 0.1 0.1 0.6 2.0
16.2 10.1 3.0 1.0 8.1 1.0 8.1 17.2 4.0 3.0 1.0 14.1
COPD, chronic obstructive pulmonary disease; OB, obliterative bronchiolitis.
5.3
0.7 2.1 0.7 5.3
0.7 0.2 1.3 3.5
1028
The Journal of Heart and Lung Transplantation, Vol 33, No 10, October 2014
Figure 8 Pediatric lung transplants. Induction immunosuppression (transplants: January 2001 to June 2013).
Figure 12 Lung transplants. Kaplan–Meier survival by recipient age group (transplants: January 1990 to June 2012).
Figure 9 Pediatric lung transplants. Kaplan–Meier survival stratified by induction use (transplants: January 2001 to June 2012).
Figure 13 Pediatric lung transplants. Kaplan–Meier survival by procedure type (transplants: January 1990 to June 2012).
Figure 10 Pediatric lung transplant recipients. Maintenance immunosuppression at time of follow-up (follow-ups: January 2001 to June 2013).
Figure 14 Pediatric lung transplants. Kaplan–Meier survival by diagnosis (transplants: January 1990 to June 2012).
Figure 11 Pediatric lung transplant recipients. Maintenance immunosuppression drug combinations at time of follow-up (follow-ups: January 2001 to June 2013).
Figure 15 Pediatric lung transplants. Kaplan–Meier survival by recipient age group (transplants: January 1990 to June 2012).
Benden et al.
ISHLT 17th Pediatric Lung and Heart–Lung Report
Figure 16 Pediatric lung transplants. Kaplan–Meier survival conditional to survival to 1 year after transplant by recipient age group (transplants: January 1990 to June 2012).
1029
Figure 19 Pediatric lung transplants. Functional status of surviving recipients (follow-ups: March 2005 to June 2013).
Table 2 Pediatric Lung Transplants: Cumulative Morbidity Rates in Survivors Within 1 Year Post-transplant (Follow-ups: April 1994 to June 2013)
Outcome
Figure 17 Pediatric lung transplants. Kaplan–Meier survival by era (transplants: January 1988 to June 2012).
Hypertension Renal dysfunction Abnormal creatinine r2.5 mg/dl Creatinine 42.5 mg/dl Chronic dialysis Renal transplant Hyperlipidemia Diabetes Bronchiolitis obliterans syndrome
Within 1 Year
Total number with known response
40.9% 9.4% 6.3%
727 756
2.0% 0.8% 0.3% 5.0% 22.2% 12.9%
746 757 700
Table 3 Pediatric Lung Transplants: Cumulative Morbidity Rates in Survivors Within 5 Years Post-transplant (Follow-ups: April 1994 to June 2013)
Outcome
Figure 18 Pediatric lung transplants. Kaplan–Meier survival by donor age for recipients age 11 to 17 years (transplants: January 1990 to June 2012).
included in this Registry report, the number of pediatric lung transplants was 93, compared with 106 in the previous year. The highest annual number of pediatric lung transplants ever reported to the Registry was 126 in 2010 (Figure 1). As in previous years, the majority of lung transplants were done in older children (11 to 17 years), with 77% of transplanted children being in this age group (Figure 1). Only 4 lung transplants were reported for recipients aged o1 year. The number of centers reporting pediatric lung transplants dropped from 43 in 2011 to 39 in 2012, with approximately half of centers located in Europe (N ¼ 20) and 15 centers in North America (Figure 2). As before, the vast majority of centers (N ¼ 34; 87%) undertook 1 to 4 procedures annually (Figure 3). For the first time in more
Hypertension Renal dysfunction Abnormal creatinine r2.5 mg/dl Creatinine 42.5 mg/dl Chronic dialysis Renal transplant Hyperlipidemia Diabetes Bronchiolitis obliterans syndrome
Within 5 years
Total number with known response
69.0% 31.3% 24.1%
210 224
4.5% 1.8% 0.9% 17.8% 35.7% 35.5%
214 224 172
than a decade, no center reported Z10 annual transplant procedures (Figure 3). The regional age distribution of pediatric lung transplants (Europe vs North America vs other) has remained unchanged with 84% of lung transplants in Europe performed in older children (Z11 years) compared with 68% in North America (Figure 4). Donor age distribution in pediatric lung transplants remains similar to findings in prior reports, with the majority
1030 Table 4
The Journal of Heart and Lung Transplantation, Vol 33, No 10, October 2014 Pediatric Lung Transplants: Cumulative Post-transplant Malignancy Rates in Survivors (Follow-ups: April 1994 to June 2013)
Malignancy/type
1-year survivors
5-year survivors
7-year survivors
No malignancy Malignancy (all types combined) Malignancy typea Lymphoma Other Type not reported
729 (94.7%) 41 (5.3%)
208 (89.3%) 25 (10.7%)
118 (90.8%) 12 (9.2%)
38 2 1
25 1 0
12 0 0
a Recipients may have had more than one type of malignancy, so the sum of individual malignancy types may be greater than total number with malignancy.
Table 5
Pediatric Lung Transplant Recipients (January 1995 to June 2012): Risk Factors for 1-Year Mortality/Graft Failure (N ¼ 852)
Variable
Number
Hazard ratio
p-value
95% confidence interval
On ventilator Diagnosis ¼ retransplanta Year of transplant: 1995 to 2002 vs 2003 to June 2012 Donor CMVþ/Recipient CMV Recipient age
147 58 354 270
2.64 2.42 1.66 1.49
o0.0001 0.0017 0.0035 0.0147 0.0210
1.72–4.07 1.39–4.19 1.18–2.34 1.08–2.05
a
Retransplant includes those with a retransplant diagnosis or a previous transplant was reported. Reference group ¼ cystic fibrosis.
Table 6
Pediatric Lung Transplant Recipients (January 1995 to June 2008): Risk Factors for 5-Year Mortality/Graft Failure (N ¼ 646)
Variable
Number
Hazard ratio
p-value
95% confidence interval
On ventilator Year of transplant: 1995 to 2001 vs 2002 to June 2008 Recipient age Pediatric transplant center volume
104 312
1.73 1.33
0.0021 0.0137 0.0095 0.0051
1.22–2.45 1.06–1.67
Table 7
Pediatric Lung Recipients: Cause of Death (Deaths: January 1992 to June 2013)
Cause of death
0–30 days (N ¼ 126)
31 days to 1 year (N ¼ 182)
41 year to 3 years (N ¼ 234)
43 years to 5 years (N ¼ 112)
45 years (N ¼ 115)
Bronchiolitis Acute rejection Lymphoma Malignancy, non-lymphoma CMV Infection, non-CMV Graft failure Cardiovascular Technical Multiple-organ failure Other
0 3 0 0 0 17 35 21 15 13 22
18 4 8 2 6 59 33 8 5 22 17
87 3 7 1 0 35 59 4 6 11 21
42 3 4 0 0 20 26 1 3 4 9
(37.5%) (2.7%) (3.6%)
55 (47.8%) 0 5 (4.3%) 5 (4.3%)
(17.9%) (23.2%) (0.9%) (2.7%) (3.6%) (8.0%)
10 22 1 2 6 9
(2.4%)
(13.5%) (27.8%) (16.7%) (11.9%) (10.3%) (17.5%)
(9.9%) (2.2%) (4.4%) (1.1%) (3.3%) (32.4%) (18.1%) (4.4%) (2.7%) (12.1%) (9.3%)
(37.2%) (1.3%) (3.0%) (0.4%) (15.0%) (25.2%) (1.7%) (2.6%) (4.7%) (9.0%)
(8.7%) (19.1%) (0.9%) (1.7%) (5.2%) (7.8%)
CMV, cytomegalovirus.
(63%) of donors o18 years of age (Figure 5). Identical to last year’s report, 6% of donors were 50 to 59 years of age and o1% were Z60 years of age (Figure 5). As reported in 2013, donor age distribution varied considerably between regions: in North America, the majority of donors used were pediatric (74%), whereas, in Europe, less than half of the donors (42%) were o18 years of age (Figure 6). There have been some changes with regard to the diagnoses leading to lung transplantation in children over
the last 2 decades, but the vast majority of transplant procedures are still carried out in children with end-stage cystic fibrosis (CF) lung disease, and there remain considerable regional differences. In North America, just over half of the pediatric lung transplant recipients had CF compared with 71% in Europe (Figure 7). Further, the distribution of underlying diagnoses in pediatric lung transplant recipients depends on the age group. In children Z11 years of age, 70% were transplanted for CF, compared with 52% in younger
Benden et al.
ISHLT 17th Pediatric Lung and Heart–Lung Report
Figure 20 Pediatric lung transplants. Freedom from bronchiolitis obliterans syndrome (follow-ups: April 1994 to June 2013).
Figure 21 Pediatric lung transplants. Freedom from bronchiolitis obliterans syndrome by age group (follow-ups: April 1994 to June 2013).
Figure 22 Pediatric lung recipients. Freedom from bronchiolitis obliterans syndrome by diagnosis (follow-ups: April 1994 to June 2013).
1031
Figure 24 Pediatric lung transplants. Kaplan–Meier survival by transplant type (transplants: January 1994 to June 2012).
Figure 25 Pediatric lung transplants. Survival by transplant type and inter-transplant interval (transplants: January 1988 to June 2012).
Figure 26 Pediatric lung retransplants. Survival by diagnosis (retransplants: January 1988 to June 2012).
children 6 to 10 years of age (Table 1). In recipients o1 year of age, surfactant protein B deficiency, congenital heart disease and idiopathic pulmonary arterial hypertension were the 3 most frequent diagnoses leading to lung transplantation, respectively (Table 1).
Immunosuppressive therapy Induction Figure 23 Pediatric lung retransplants (retransplants: January 1994 to June 2013).
Compared with the previous year, there is no change regarding the use of induction immunosuppression in
1032
The Journal of Heart and Lung Transplantation, Vol 33, No 10, October 2014
pediatric lung transplantation. The majority of children (62%) received induction treatment, generally with an interleukin-2 (IL-2) receptor antagonist (48% of all patients) (Figure 8). As previously described,2 there was no significant survival difference seen when recipients were stratified by induction use (Figure 9).
Maintenance A triple maintenance immunosuppressive treatment, including a calcineurin inhibitor (CNI), mycophenolate mofetil/mycophenolic acid (MMF/MPA) and prednisone, was the most common maintenance immunosuppression regimen for children after lung transplantation (Figures 10 and 11). Tacrolimus was the most commonly prescribed CNI in children in the first year after transplant (84% of cases) (Figure 10). MMF/ MPA was the first choice of cell-cycle inhibitor, used in almost 70% of cases at 1 year after transplantation, with 62% receiving it in combination with tacrolimus (Figures 10 and 11). Even at 5-year follow-up, half the children were on tacrolimus plus MMF/MPA as maintenance therapy (Figure 11). The number of pediatric recipients on a combination of tacrolimus plus sirolimus/everolimus at 5 years post-transplant has reached 8% (Figure 11). Similar to the previous year’s report,2 490% of children received prednisone at 5 years post-transplant (Figure 10).
Outcomes of primary transplants Survival in children after lung transplantation is similar to that reported in adults with a median survival of 5.1 vs 5.6 years, respectively, for patients transplanted between January 1990 and June 2012 (Figure 12). Survival after bilateral/double pediatric lung transplantation (N ¼ 1,654) is better than that after single lung transplantation (N ¼ 94), with a median survival of 5.5 vs 1.9 years, respectively (Figure 13). No statistical difference in survival was seen between recipients transplanted for CF compared with those transplanted for non-CF diagnoses (Figure 14). Although the comparison is not statistically significant, overall and 1-year conditional survival rates in children Z11 years of age were numerically lower compared with younger transplant recipients (Figures 15 and 16). Survival of pediatric lung recipients in the 2 most recent eras (2000 to 2005 and 2006 to June 2012) was superior to the previous era of 1988 to 1999, but there was no significant difference in survival between the 2 most recent eras 2000 to 2005 and 2006 to June 2012) (Figure 17). Survival of recipients 11 to 17 years old at the time of transplant stratified by donor age is shown in Figure 18. Although no pairwise comparisons were statistically significant, there was a numerical trend for worse survival in the group of pediatric recipients who received lungs from older donors.
physician, with 480% of surviving children followed-up between 2005 and 2013 having a functional status of Z80% for Lansky score through 3 years post-transplant (Figure 19).
Complications and morbidities At 1-year post-transplant, hypertension was the most common morbidity in 440% of surviving children, followed by diabetes mellitus (22%) and bronchiolitis obliterans syndrome (BOS) (13%) (Table 2). More than two thirds of children within 5 years post-transplant (followups: April 1994 to June 2013) were reported to have hypertension (Table 3). Diabetes mellitus (36%), BOS (35%) and chronic renal impairment (31%) were also frequent morbidities within 5 years post-transplant (Table 3). Further details of the cumulative prevalence of morbidities are presented in Tables 2 and 3. At 5 years posttransplant, 11% of surviving transplant recipients were diagnosed with a malignancy, and almost all malignancies were lymphomas (Table 4). Significant risk factors for 1-year mortality or graft failure were pre-transplant ventilator use, retransplantation, earlier transplantation era, cytomegalovirus (CMV), high-risk donor/recipient mismatch (Table 5) and older recipient age (Table 6).
Bronchiolitis obliterans syndrome BOS, the most common form of chronic lung allograft dysfunction, remains the most frequent overall cause of morbidity, with a prevalence of 450% in surviving transplant recipients by 5 years post-transplant (Figure 20). There was a trend for higher cumulative incidence of BOS in children transplanted at Z11 years of age compared with younger recipients. Almost 60% of recipients transplanted at age Z11 years had BOS by 5 years post-transplant (Figure 21). There was also a trend for lower freedom from BOS in surviving CF recipients compared with recipients transplanted for idiopathic pulmonary arterial hypertension (IPAH)—45% vs 57% at 5 years post-transplant, respectively (Figure 22).
Cause of death The most common cause of death early after transplantation (within the first 30 days) remains graft failure, occurring in 28% of cases (Table 7). Up to 1 year after transplantation, non-CMV infection was the leading cause of death, occurring in 32% of recipients. Beyond the first year posttransplant, BOS has remained, by far, the primary cause of death (deaths: January 1992 to June 2013), with this figure increasing from 37% between 1 and 5 years post-transplant to 48% of deaths at 45 years post-transplant (Table 7).
Functional status
Retransplantation
Overall functional status of children after lung transplantation remained good, as reported by the
This report has focused on an overall theme of retransplantation. In almost 2 decades (January 1994 to June 2013),
Benden et al.
ISHLT 17th Pediatric Lung and Heart–Lung Report
a total of only 106 retransplants were reported in pediatric lung transplant recipients (Figure 23). The vast majority of retransplants were performed beyond 1 year after the primary transplant procedure (Figure 23). In approximately half of these cases, retransplants were undertaken for obliterative bronchiolitis. Between January 1990 and June 2013, 77% of retransplants were carried out in patients 11 to 17 years of age. In recipients with obliterative bronchiolitis, 71% (40 of 56) of retransplants were done in recipients Z11 years old (Table 1), similar to figures in recipients with indications other than obliterative bronchiolitis—60 of 75 (80%) recipients Z11 years old (note: Table 1 does not identify all retransplants with other indications). Retransplant as the diagnosis leading to lung transplantation in children was slightly less common in Europe (4% of all transplants) compared with North America (7% of all transplants carried out between January 2000 and June 2013 (Figure 7). Survival after retransplantation (N ¼ 116) was significantly inferior compared with all primary lung transplant procedures (N ¼ 1,490) performed from January 1994 to June 2012 (Figure 24). In this period, 1- and 5-year survival rates for patients after primary transplant were 82% and 52%, respectively, compared with 57% and 33%, respectively, for patients after retransplantation (Figure 24). Survival after retransplantation remained significantly inferior compared with primary transplants, even if retransplant procedures were stratified by inter-transplant interval (Figure 25). Although the difference did not reach statistical significance, perhaps due to the small number of patients and events, 1-year survival for retransplants undertaken o1 year after the primary transplant (N ¼ 34) was half that of retransplants done Z1 year after the primary transplant (N ¼ 82)—32% and 61%, respectively (Figure 25). The analyses were limited to patients o18 years of age at time
1033
of retransplant, and included deceased as well as living donors. Survival after retransplant was not significantly different if stratified by diagnosis (obliterative bronchiolitis, N ¼ 60, vs non-obliterative bronchiolitis, N ¼ 66) (Figure 26). In conclusion, this 2014 ISHLT Registry report on pediatric lung transplantation shows favorable survival in children undergoing lung transplantation as the ultimate therapy for end-stage lung diseases, with results of lung transplantation in children comparable to those seen in adult recipients. To date, however, BOS continues to be the greatest obstacle to improved long-term outcomes across all age groups. Retransplantation remains the last therapy option, generally for patients with progressive BOS, as acceptable outcomes after retransplantation seem achievable only in highly selected candidates. Thus, the number of pediatric lung retransplant procedures reported to the Registry has remained low.
Disclosure statement All relevant disclosures for the Registry Director, Executive Committee Members and authors are on file with the ISHLT and can be made available for review by contacting the Executive Director of the ISHLT.
References 1. Benden C, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Fifteenth Pediatric Lung and Heart–Lung Transplantation Report—2012. J Heart Lung Transplant 2012;31:1087-95. 2. Benden C, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Sixteenth Official Pediatric Lung and Heart–Lung Transplantation Report—2013. J Heart Lung Transplant 2013;32:989-97.
