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The Registry of the International Society for Heart and Lung Transplantation: Eighteenth Official Pediatric Lung and Heart-Lung Transplantation Report—2015; Focus Theme: Early Graft Failure
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The Registry of the International Society for Heart and Lung Transplantation: Eighteenth Official Pediatric Lung and Heart-Lung Transplantation Report—2015; Focus Theme: Early Graft Failure Samuel B. Goldfarb, MD, Christian Benden, MD, Leah B. Edwards, PhD, Anna Y. Kucheryavaya, MS, Anne I. Dipchand, MD, FRCPC, Bronwyn J. Levvey, RN, Lars H. Lund, MD, PhD, Bruno Meiser, MD, Joseph W. Rossano, MD, Roger D. Yusen, MD, MPH, and Josef Stehlik, MD, MPH; for the International Society for Heart and Lung Transplantation From the International Society for Heart and Lung Transplantation Thoracic Transplant Registry, Dallas, Texas.
This section of the International Society for Heart and Lung Transplantation (ISHLT) 18th Official Registry Report of 2015 summarizes data from pediatric (o18 years) lung transplant recipients and their donors for transplants that occurred through June 30, 2014. 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 early graft failure (EGF). The report incorporates new EGFrelated analyses, figures, and tables into the annual update. Data on heart-lung transplantation in children are not presented in this year’s report because the number of pediatric heart-lung transplant procedures remained very low. Only 11 pediatric heart-lung transplant procedures performed in 2013 were reported to the Registry. Data on pediatric heart-lung transplantation were presented in 2012.1 All updated slides on pediatric heart-lung transplantation are available online (www.ishlt.org/registries).
Reprint requests: Josef Stehlik, MD, MPH, Division of Cardiovascular Medicine, 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: þ1-801-585-2340. Fax: þ1-801-581-7735. E-mail address: [email protected] 1053-2498/$ - see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.healun.2015.08.005
Data collection and statistical methods Data are submitted to the ISHLT Registry by national and multinational organ/data exchange organizations and individual centers. Since the Registry’s inception, 418 heart transplant centers, 242 lung transplant centers, and 174 heart-lung transplant centers have reported data. The Registry Web site (www.ishlt.org/registries) provides spreadsheets that show data elements collected in the Registry. The online slide set (http://www.ishlt.org/registries/slides.asp?slides¼heartLungRegistry) provides PowerPoint (Microsoft Corp) slides of figures and tables that support this report. The site contains additional slides for this report and slide sets from the previous annual reports.
General methods This report used standard statistical methodology for analyses and reporting. For assessing time-to-event rates (e.g., survival), we used the Kaplan-Meier method. Survival graphs (i.e., time-to-event graphs) were truncated when the number of analyzable individuals was fewer than 10. Follow-up of surviving recipients was censored at the time last reported to be alive (i.e., most recent annual follow-up) or at the time of retransplantation. Median time-to-event estimated the point at which 50% of all recipients experienced the outcome event (e.g., death). Conditional
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Table 1 Early Graft Failure in Pediatric Lung Transplant Recipients, for Transplants Performed January 2005 to December 2013, Stratified by Source of Graft Failure
Table 2 Death or Graft Failure in Pediatric Lung Transplants Performed January 2005–December 2013, Stratified by Cause, Where the Early Mortality or Graft Failure Did Not Meet the Early Graft Failure Definition
Pediatric patients Source of graft failure Death
Retransplant
Reason of graft failure
No. (%)
Total Graft failure Graft infection Non-specific Primary failure Acute rejection Viral infection (other specify) Respiratory failure Reported as unknown Total Graft failure/dysfunction
18 100.0 1 1 3 1 2
5.6 5.6 16.7 5.6 11.1
4 22.2 6 33.3 2 100.0 2 100.0
analyses included only those transplant recipients who met the required criterion (e.g., survival past 1 year posttransplant). We used the log-rank test to compare survival curves among groups. To prevent spuriously statistically significant findings, we adjusted all pairwise tests for multiple comparisons (Scheffé or Bonferroni tests). For multivariable time-to-event analyses, we used Cox proportional hazards regression. These analyses used the censoring approaches described above. Cox models only included transplant recipients who had data available for most of the risk factors in the final model. The nonconditional models used the latest data available at the time of the transplant. In contrast to non-conditional analyses, the conditional analyses also adjusted for post-transplant factors. 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 and corresponding 95% confidence intervals and p-values. Tables and forest plots show hazard ratios and 95% confidence intervals for categoric variables in the final models. A more detailed explanation of the analytical methodology is available online (www.ishlt.org/registries) and in previous annual reports.2–5 This report refers to specific online eSlides when particular data are discussed but not shown due to space limitations; eSlide numbers refer to the online pediatric lung slides. We recommend interpretation of unadjusted analyses and predictive/comparative risk models in the context of the limitations typical of registry data.
Focus theme methods For this report, the Registry Steering Committee selected the focus theme of EGF. The granularity of data collected in the Registry influenced the definition of EGF. We defined EGF as a composite end point of death or retransplant associated with graft failure within the first 30 days after transplant. Death or retransplant events associated with causes we
Pediatric patients Source of graft failure
Reason of graft failure
Death (not EGF) Total Cardiovascular Cardiac arrest Cardiogenic shock Other specify Ventricular failure Cerebrovascular Other specify Stroke Hemorrhage Intraoperative Other specify Post-operative Immunosuppressive drugrelated–hematologic Infection Bacterial septicemia Fungal, other specify Other specify Multiple organ failure Not reported Graft failure Total r 30 daysa Adenoviral pneumonitis Not reported
No. % 36 100.0 3 1 4 2
8.3 2.8 11.1 5.6
1 3
2.8 8.3
1 4 2 1
2.8 11.1 5.6 2.8
3 8.3 1 2.8 2 5.6 7 19.4 1 2.8 4 100.0 1 3
25.0 75.0
EGF, early graft failure. a But not death or retransplant r30 days.
believed were not due to intrinsic graft failure were excluded from the EGF definition. Because our EGF definition required an association between these outcome events and graft failure, rather than all-cause death or allcause retransplant, death or retransplant events that did not meet the EGF criteria occurred in a large number of transplant recipients. In addition, if the center reported the cause for a transplant recipient’s death or retransplant as “unknown,” we counted the recipient as having EGF. If the center did not report a cause for a transplant recipient’s death or retransplant (i.e., field was left blank), we did not count the recipient as having EGF. Of note, the composite end point excluded graft failure that did not lead to death or retransplant within 30 days, although such events were rarely reported. The definition of EGF in this report certainly differs from the definition of primary graft dysfunction in thoracic transplantation and reflects the most severe sub-group of early graft injury resulting in graft loss. For estimating the cumulative incidence of EGF at 30 days and the percentage of transplant recipients that developed EGF within 30 days, we used a competing risks extension of the Kaplan-Meier method. Competing events
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1257 0-10 years
11-17 years
18-34 years
35-49 years
50-59 years
60+ years
100%
% of Donors
80%
60%
40%
20%
0% North America (N=352)
Europe (N=321)
Figure 1 Pediatric lung recipients. Recipient age distribution by year of transplant. Analysis includes deceased and living donor transplants. ISHLT, International Society for Heart and Lung Transplantation.
Other (N=45)
Figure 4 Pediatric lung transplants. Donor age distribution by location (transplants: January 2008—June 2014). The analysis excluded transplants with unknown donor age and living donor transplants.
Cystic Fibrosis
IPAH
IPF
BOS
Other
Congenital heart disease
Retx
100%
% of Transplants
80%
60%
40%
20%
0% Europe (N=311)
Figure 2 Pediatric lung transplants. Number of centers reporting transplants by location.
North America (N=351)
Other (N=52)
Figure 5 Pediatric lung transplants. Diagnosis distribution by location (transplants: January 2008–June 2014). BOS, bronchiolitis obliterans syndrome; IPAH, idiopathic pulmonary artery hypertension; IPF, interstitial pulmonary fibrosis; Retx, retransplant.
100
Induction (N = 209)
Survival (%)
No Induction (N = 92)
75
50 p=0.9444
25
0
0
1
2
3
4
5
Years
Figure 6 Pediatric lung transplants. Kaplan-Meier survival stratified by induction use (transplants: January 2008–June 2013). Figure 3 Pediatric lung transplants. Recipient age distribution by location (transplants: January 2008–June 2014).
consisted of death or retransplant within 30 days posttransplant and not meeting the EGF criteria or graft failure not associated with death or retransplant. We used consistent EGF definitions for the pediatric and adult age groups within each organ (heart and lung). However, causes of death or retransplant that were included in the definition of EGF differed between heart and lung transplant. The causes of death and causes of retransplant leading to death within 30 days of lung transplant are listed in Tables 1 and 2.
Volume, age distribution, indications, and donor characteristics Since 1986, 2,091 pediatric lung transplants and 689 pediatric heart-lung transplants were performed and included in the Registry. In 2013, the last complete year included in this year’s Registry report, the number of pediatric lung transplants increased to 124 compared with 95 in the previous year (Figure 1).6 As in previous years, most lung transplants were done in older children (11–17 years). In 2013, 75% of children who received transplants were aged Z11 years, whereas only 3 lung transplants in infants (o1 year) were performed.
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Table 3
Indications for Pediatric Lung Transplants by Age Group (Transplants: January 2000–June 2014)
Diagnosis Cystic fibrosis IPAH Obliterative bronchiolitis Retransplant No retransplant Congenital heart disease Pulmonary fibrosis Idiopathic Other Retransplant, not obliterative bronchiolitis Interstitial pneumonitis Pulmonary vascular disease Eisenmenger’s syndrome Surfactant protein B deficiency COPD/emphysema Bronchopulmonary dysplasia Bronchiectasis Other
o1 year
1–5 years
6–10 years
11–17 years
No. (%)
No. (%)
No. (%)
No. (%)
0 (0) 7 (13.0)
5 (5.7) 19 (21.8)
99 (50.5) 20 (10.2)
726 (69.1) 83 (7.9)
0 (0) 0 (0) 8 (14.8)
4 (4.6) 8 (9.2) 7 (8.0)
6 (3.1) 21 (10.7) 3 (1.5)
33 (3.1) 48 (4.6) 8 (0.8)
8 15 3 2 2 1 0 0 1 0 12
29 28 24 1 1 4 0 0 6 14 43
4 7 0 0 2 0 11 0 4 0 11
(7.4) (13.0) (0) (0) (3.7) (0) (20.4) (0) (7.4) (0) (20.4)
11 10 4 2 5 1 4 0 2 0 5
(12.6) (11.5) (4.6) (2.3) (5.7) (1.1) (4.6) (0) (2.3) (0) (5.7)
(4.1) (7.7) (1.5) (1.0) (1.0) (0.5) (0) (0) (0.5) (0) (6.1)
(2.8) (2.7) (2.3) (0.1) (0.1) (0.4) (0) (0) (0.6) (1.3) (4.1)
COPD, chronic obstructive pulmonary disease; IPAH, idiopathic pulmonary arterial hypertension.
100 Year 1 (N = 277)
% of patients
80
Year 5 (N = 142)
60
40
20
0 Cyclosporine
Tacrolimus
Sirolimus/ Everolimus
MMF/MPA
Azathioprine
Prednisone
Figure 7 Pediatric lung recipients. Maintenance immunosuppression at the time of follow-up (follow-ups: January 2008–June 2014). The analysis was limited to patients who were alive at the follow-up. MMF/MPA, mycophenolate mofetil/mycophenolic acid.
100% Other
% of Patients
80%
Tacrolimus + Sirolimus/Everolimus Tacrolimus
60% Tacrolimus + MMF/MPA
40%
Tacrolimus + AZA Cyclosporine + MMF/MPA
20%
Cyclosporine + AZA
0%
Year 1 (N = 277)
Year 5 (N = 142)
NOTE: Different patients are analyzed in Year 1 and Year 5.
Figure 8 Pediatric lung recipients. Maintenance immunosuppression drug combinations at the time of follow-up (follow-ups: January 2008–June 2014). The analysis was limited to patients who were alive at the time of the follow-up. AZA, azathioprine; MMF/MPA, mycophenolate mofetil/mycophenolic acid.
Figure 9 Adult and pediatric lung transplants. Kaplan-Meier survival by recipient age group (transplants: January 1990– June 2013).
The age distribution of recipients has remained relatively constant (Figure 1). The number of centers reporting pediatric lung transplants in 2013 increased to 45 from 40 in 2012, with 20 centers located in Europe, 22 centers located in North America, and 3 centers located in other areas (Figure 2). As before, most centers (38 [84%]) conducted 1 to 4 procedures annually, 5 centers performed between 5 to 9 procedures, and 2 centers performed 4 10 procedures (eSlide 13). Fifty percent of the transplants performed occurred in centers that do Z 5 procedures annually. The age distribution of pediatric lung transplants differs by location, with 81% of lung transplants in Europe performed in older children (Z11 years) compared with 67% in North America (Figure 3). Most (58%) of donors are aged o 18 years, with o 10% of the donors aged 4 50 years (Figure 4). The donor age distribution varies considerably between regions: in North America, 76% of donors were pediatric, whereas in Europe
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Figure 10 Pediatric lung transplants. Kaplan-Meier survival by recipient age group (transplants: January 1990–June 2013).
Figure 11 Pediatric lung transplants. Kaplan-Meier survival conditional to recipient survival to 1 year after transplant shown by recipient age group (transplants: January 1990–June 2013). Conditional median survival is defined as median survival limited to patients surviving to 1 year after transplant.
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Figure 14 Pediatric lung transplants. Recipient age and hazard of 1-year mortality/graft failure (January 1996–June 2013).
Figure 15 Pediatric lung transplants. Recipient age and hazard of 5-year mortality/graft failure (transplants: January 1996– June 2009).
Figure 12 Pediatric lung transplants. Kaplan-Meier survival by era (transplants: January 1988–June 2013). Conditional survival is defined as median survival limited to patients surviving to 1 year after transplant.
Figure 16 Pediatric lung transplants. Freedom from bronchiolitis obliterans syndrome (follow-ups: April 1994–June 2014).
Figure 13 Pediatric lung transplants. Kaplan-Meier survival by donor age for recipients aged 11 to 17 years (transplants: January 1990–June 2013).
Figure 17 Pediatric lung transplants. Freedom from bronchiolitis obliterans syndrome by age group (follow-ups: April 1994– June 2014).
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Table 4 Cumulative Morbidity Rates in Pediatric Lung Transplant Survivors Within 1, 5, and 7 Years After Transplant (Follow-ups: April 1994–June 2014)
Outcome a
Hypertension Renal dysfunction Creatinine, mg/dl r2.5 (abnormal) 42.5 Chronic dialysis Renal transplant Hyperlipidemiaa Diabetesa BOS
Within 1 year
Total with known response
Within 5 years
Total with known response
Within 7 years
Total with known response
(%)
(No.)
(%)
(No.)
(%)
(No.)
41.4 9.4
765 795
67.7 29.6
229 247
… 42.8
… 138
781 797 739
23.1 4.0 1.6 0.8 17.7 35.2 35.9
231 250 192
32.6 6.5 0.7 2.9 … … 41.9
… … 93
6.5 1.9 0.8 0.3 5.1 21.3 12.2
BOS, bronchiolitis obliterans syndrome. a Data are not available 7 years post-transplant.
Table 5
Cumulative Post-transplant Malignancy Rates in Pediatric Lung Transplants Survivors (Follow-ups: April 1994–June 2014) 1-year survivors
5-year survivors
7-year survivors
Malignancy and type
No. (%)
No. (%)
No. (%)
No malignancy Malignancy (all types combined) Malignancy typea Lymphoma Other Type not reported
770 (95.1) 40 (4.9)
231 (89.5) 27 (10.5)
132 (91) 13 (9%)
a
38 2 0
26 1 1
13 0 0
Recipients may have experienced 41 type of malignancy, so the sum of individual malignancy types may exceed the total number with a malignancy.
Table 6
Cause of Death in Pediatric Lung Transplant Recipients (Deaths: January 2000–June 2014) 0-30 days (n ¼ 76)
31 days–1 year (n ¼ 120)
41–3 years (n ¼ 182)
43–5 years (n ¼ 100)
45 years (n ¼ 121)
Cause of death
No. (%)
No. (%)
No. (%)
No. (%)
No. (%)
Bronchiolitis Acute rejection Lymphoma Malignancy, non-lymphoma CMV Infection, non-CMV Graft failure Cardiovascular Technical Multiorgan failure Other
0 3 (3.9) 0 0 0 13 (17.1) 10 (13.2) 13 (17.1) 10 (13.2) 13 (17.1) 14 (18.4)
14 2 3 2 2 34 25 6 3 19 10
65 5 3 1 0 25 51 3 3 11 15
39 2 4 0 0 16 24 1 3 4 7
55 0 5 6 0 8 28 1 2 7 9
(11.7) (1.7) (2.5) (1.7) (1.7) (28.3) (20.8) (5.0) (2.5) (15.8) (8.3)
(35.7) (2.7) (1.6) (0.5) (13.7) (28.0) (1.6) (1.6) (6.0) (8.2)
(39.0) (2.0) (4.0)
(16.0) (24.0) (1.0) (3.0) (4.0) (7.0)
(45.5) (4.1) (5.0) (6.6) (23.1) (0.8) (1.7) (5.8) (7.4)
CMV, cytomegalovirus.
and in other centers, 41% and 47%, respectively, were aged o18 years (Figure 4). There have not been significant changes during the past 2 decades in the diagnoses leading to lung transplants in children.3 Most transplant procedures are performed in children with cystic fibrosis (CF) lung disease; in addition,
there are considerable regional differences (Figure 5). In North America, 49% of the pediatric lung transplant recipients have CF compared with 68% in Europe (Figure 5). Further, the distribution of underlying diagnoses in pediatric lung transplant recipients depends on their age group. In children aged Z 11 years, 69% have CF compared
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ISHLT 18th Pediatric Lung and Heart–Lung Report
with 51% in younger children aged 6 to 10 years (Table 3). In recipients aged o 1 year, the combined forms of pulmonary fibrosis, surfactant protein B deficiency, congenital heart disease, and idiopathic pulmonary arterial hypertension were the 4 most frequent diagnoses leading to lung transplantation (Table 3).
Immunosuppressive therapy Induction The use of induction immunosuppression in pediatric lung transplantation is similar to last year’s report.3 Most children (68%) received induction treatment, of which 54% were treated with an interleukin-2 receptor antagonist (eSlide 35). A similar proportion of pediatric heart transplant recipients received induction therapy (68%); however, only 24% received induction with an interleukin-2 receptor antagonist, and 48% received anti-thymocyte globulin.7 There was no significant survival benefit for pediatric lung transplant recipients who received induction (Figure 6).
Maintenance A triple-maintenance immunosuppressive treatment including a calcineurin inhibitor, cell-cycle inhibitor, and prednisone was the most common maintenance immunosuppression regimen for children after lung transplantation. Tacrolimus is prescribed in 97% of children in the first year after transplant in (Figure 7). Mycophenolate mofetil/mycophenolic acid was the first choice of cell-cycle inhibitor, used in 82% of patients at 1 year after transplantation, with 78% of all patients receiving it in combination with tacrolimus. At the 5-year follow-up, 61% of children were receiving tacrolimus and mycophenolate mofetil/mycophenolic acid as maintenance (Figure 8). The number of pediatric recipients receiving a combination of tacrolimus and sirolimus/everolimus at 5 years post-transplant is low, at 4% (Figure 8). More than 90% of children received prednisone at 5 years post-transplant.
Outcomes of primary transplants Survival Survival in children after lung transplantation was similar to that reported in adults, with a median survival of 5.3 vs 5.6 years, respectively, for patients who received transplants between January 1990 and June 2013 (Figure 9). There was a significantly superior survival after bilateral/ double pediatric lung transplants (n ¼ 1,762) compared with single-lung transplants (n ¼ 88), with a median unadjusted survival of 5.6 vs 2.2 years, respectively (eSlide 22). No statistical difference existed between overall survival of CF recipients and non-CF recipients (eSlide 23). Although overall survival and survival conditional to recipient survival to 1 year after transplant was numerically lower in children aged Z 11 years, this difference was not statistically significant (Figures 10 and 11). There was a
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statistically significant improvement in survival comparing the most recent eras (since 2000) with the earlier transplant era of 1988 to 1999, but survival did not improve significantly when the 2 most recent eras—2000 to 2007 vs. 2008 to June 2013—were compared (Figure 12). Although survival of recipients aged 11 to 17 years appears inferior if older donors (Z 50 years) were used, pair-wise comparisons were not significantly different (p o 0.05; Figure 13).
Functional status Overall functional status of children after lung transplantation remained good as reported by the physician. More than 80% of surviving children followed up between January 2008 and June 2014 had a functional status of Z80% Lansky score through 3 years post-transplant (eSlide 31).
Complications and morbidities At 1-year post-transplant (follow-ups: April 1994–June 2014), hypertension was the most common morbidity in 440% of surviving children, followed by diabetes mellitus in 21% and bronchiolitis obliterans syndrome (BOS) in 12% (Table 4). Hypertension was reported in approximately 68% of children within 5 years post-transplant. Other frequent morbidities within 5 years post-transplant were diabetes mellitus (35%), BOS (36%), and chronic kidney dysfunction (30%). Additional details of the cumulative prevalence of morbidities are reported in Table 4. At 5 years posttransplant, 90% of surviving transplant recipients had no malignancies. Almost all malignancies in pediatric lung transplant recipients within 5 years of transplant were lymphomas (Table 5). Unlike adult lung transplant recipients, pediatric transplant recipients rarely develop skin cancer.2 Significant categoric risk factors for 1-year mortality or graft failure were pre-transplant ventilator use, retransplantation, earlier era of transplantation, and cytomegalovirus high-risk donor/recipient mismatch (eSlide 60). Significant categoric risk factors for 5-year mortality or graft failure included retransplantation and earlier era of transplantation (eSlide 63). These risk factors were also similar to mortality risk factors seen in the adult lung transplant recipients.2 The hazard of 1-year post-transplant mortality with regard to recipient age was fairly linear throughout the pediatric recipient age range, with higher age representing higher risk (Figure 14). The association of recipient age with 5-year post-transplant survival was also significant; however, the association had a U-shaped appearance (Figure 15).
Bronchiolitis obliterans syndrome BOS, the most common form of chronic lung allograft dysfunction, is the most frequent overall cause of morbidity, with a prevalence of 450% of surviving transplant recipients by 5 years post-transplant (Figure 16). Though BOS appeared to be more common in 11- to 17-year-olds, with 60% affected by 5 years post-transplant, no pair-wise
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Figure 18 Pediatric lung transplants. Cumulative incidence of early graft failure (EGF) by transplant type (transplants: January 2005–December 2013).
Figure 19 Pediatric lung transplants. Percentage with early graft failure (EGF) by EGF type and year for primary transplants (primary transplants: January 2005–December 2013).
Figure 20 Pediatric lung transplants. Cumulative incidence of early graft failure (EGF) by diagnosis and era (primary transplants: January 2005–December 2013). CF, cystic fibrosis.
10% Death
% of transplants with EGF
9%
Retransplant
8% 7%
No pair-wise comparisons of % with EGF significant at p < 0.05.
6% 5% 4%
Figure 22 Pediatric lung transplants. Cumulative incidence of early graft failure (EGF) by donor age group (transplants: January 2005–December 2013).
Figure 23 Pediatric lung transplants. Cumulative incidence of early graft failure (EGF) by gender (primary transplants: January 2005–December 2013).
Figure 24 Pediatric lung transplants. Percentage of recipients with early graft failure (EGF) by EGF type and center volume (primary transplants: January 2005–December 2013).
comparisons were significant (Figure 17). There was a significant statistical difference with regard to freedom from BOS in surviving CF recipients compared with recipients with idiopathic pulmonary hypertension, with 44% vs 56% freedom from BOS at 5 years, respectively (p ¼ 0.043; eSlide 48).
3% 2%
Causes of death
1% 0% 0-5 years (N=126)
6-10 years (N=702)
11-17 years (N=102)
Figure 21 Pediatric lung transplants. Percentage of recipients with early graft failure (EGF) by EGF type and age group (primary transplants: January 2005–December 2013).
The most common causes of deaths that occurred in the era January 2000 to June 2014 within the first 30 days after transplantation were cardiovascular and multiorgan failure, representing 34% of all cases (Table 6). Up to 1 year after
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transplant, non-cytomegalovirus infection was the leading cause of death in 24%.5,6 Beyond the first year after transplant, BOS and graft failure are by far the major causes of death: BOS represented 39% and 45% of deaths between 3 and 5 years and at 4 5 years, respectively, and graft failure represented 24% and 23% of deaths at 3 to 5 years and at 4 5 years, respectively (Table 6).
Disclosure statement
Early graft failure
References
This Registry report focuses on an overall theme of EGF. The incidence of EGF in primary transplants during the first 30 days after transplant was between 1% and 2% of recipients. The incidence of EGF for retransplant recipients was significantly greater, reaching 9% at 30 days after transplant (Figure 18). The number of recipients per year with EGF has remained fairly constant during the past 9 years, ranging from 0 to 4 occurrences per year (Figure 19). Further, during this same interval, there has been no significant era effect or difference between CF and non-CF transplant recipients in the incidence of EGF (Figure 20) and no significant difference in EGF rates between age groups (Figure 21), donor age groups (Figure 22), recipient gender (Figure 23), or center volume (Figure 24). In conclusion, the 2015 ISHLT Registry Report on Pediatric Lung Transplantation shows further improvements in survival in children undergoing lung transplantation, with results of lung transplantation in children comparable with results seen in adult recipients. To date, however, BOS continues to be the most important obstacle for better longterm outcomes across all age groups. The incidence of EGF has been 1% to 4% during the past 9 years. We identified retransplant as the strongest risk factor for EGF after pediatric lung transplantation. No clear associations with other donor or recipient characteristics were apparent.
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. Yusen RD, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart-lung transplant report—2014; focus theme: retransplantation. J Heart Lung Transplant 2014;33:1009-24. 3. Lund LH, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-first official adult heart transplant report—2014; focus theme: retransplantation. J Heart Lung Transplant 2014;33:996-1008. 4. Dipchand AI, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: seventeenth official pediatric heart transplantation report—2014; focus theme: retransplantation. J Heart Lung Transplant 2014;33:985-95. 5. Benden C, Goldfarb SB, Edwards LB, et al. The registry of the International Society for Heart and Lung Transplantation: seventeenth official pediatric lung and heart-lung transplantation report—2014; focus theme: retransplantation. J Heart Lung Transplant 2014;33: 1025-33. 6. 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; focus theme: age. J Heart Lung Transplant 2013;32:989-97. 7. Dipchand A, Rossano JW, Edwards LB, et al. The Registry of the International Society for Heart and Lung Transplantation: Eighteenth Official Pediatric Heart Transplantation Report — 2015; Focus Theme: Early Graft Failure. J Heart Lung Transplant 2015;34:1233-43.
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.
The Registry of the International Society for Heart and Lung Transplantation: Eighteenth Official Pediatric Lung and Heart-Lung Transplantation Report—2015; Focus Theme: Early Graft Failure Samuel B. Goldfarb, MD, Christian Benden, MD, Leah B. Edwards, PhD, Anna Y. Kucheryavaya, MS, Anne I. Dipchand, MD, FRCPC, Bronwyn J. Levvey, RN, Lars H. Lund, MD, PhD, Bruno Meiser, MD, Joseph W. Rossano, MD, Roger D. Yusen, MD, MPH, and Josef Stehlik, MD, MPH; for the International Society for Heart and Lung Transplantation From the International Society for Heart and Lung Transplantation Thoracic Transplant Registry, Dallas, Texas.
This section of the International Society for Heart and Lung Transplantation (ISHLT) 18th Official Registry Report of 2015 summarizes data from pediatric (o18 years) lung transplant recipients and their donors for transplants that occurred through June 30, 2014. 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 early graft failure (EGF). The report incorporates new EGFrelated analyses, figures, and tables into the annual update. Data on heart-lung transplantation in children are not presented in this year’s report because the number of pediatric heart-lung transplant procedures remained very low. Only 11 pediatric heart-lung transplant procedures performed in 2013 were reported to the Registry. Data on pediatric heart-lung transplantation were presented in 2012.1 All updated slides on pediatric heart-lung transplantation are available online (www.ishlt.org/registries).
Reprint requests: Josef Stehlik, MD, MPH, Division of Cardiovascular Medicine, 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: þ1-801-585-2340. Fax: þ1-801-581-7735. E-mail address: [email protected] 1053-2498/$ - see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.healun.2015.08.005
Data collection and statistical methods Data are submitted to the ISHLT Registry by national and multinational organ/data exchange organizations and individual centers. Since the Registry’s inception, 418 heart transplant centers, 242 lung transplant centers, and 174 heart-lung transplant centers have reported data. The Registry Web site (www.ishlt.org/registries) provides spreadsheets that show data elements collected in the Registry. The online slide set (http://www.ishlt.org/registries/slides.asp?slides¼heartLungRegistry) provides PowerPoint (Microsoft Corp) slides of figures and tables that support this report. The site contains additional slides for this report and slide sets from the previous annual reports.
General methods This report used standard statistical methodology for analyses and reporting. For assessing time-to-event rates (e.g., survival), we used the Kaplan-Meier method. Survival graphs (i.e., time-to-event graphs) were truncated when the number of analyzable individuals was fewer than 10. Follow-up of surviving recipients was censored at the time last reported to be alive (i.e., most recent annual follow-up) or at the time of retransplantation. Median time-to-event estimated the point at which 50% of all recipients experienced the outcome event (e.g., death). Conditional
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Table 1 Early Graft Failure in Pediatric Lung Transplant Recipients, for Transplants Performed January 2005 to December 2013, Stratified by Source of Graft Failure
Table 2 Death or Graft Failure in Pediatric Lung Transplants Performed January 2005–December 2013, Stratified by Cause, Where the Early Mortality or Graft Failure Did Not Meet the Early Graft Failure Definition
Pediatric patients Source of graft failure Death
Retransplant
Reason of graft failure
No. (%)
Total Graft failure Graft infection Non-specific Primary failure Acute rejection Viral infection (other specify) Respiratory failure Reported as unknown Total Graft failure/dysfunction
18 100.0 1 1 3 1 2
5.6 5.6 16.7 5.6 11.1
4 22.2 6 33.3 2 100.0 2 100.0
analyses included only those transplant recipients who met the required criterion (e.g., survival past 1 year posttransplant). We used the log-rank test to compare survival curves among groups. To prevent spuriously statistically significant findings, we adjusted all pairwise tests for multiple comparisons (Scheffé or Bonferroni tests). For multivariable time-to-event analyses, we used Cox proportional hazards regression. These analyses used the censoring approaches described above. Cox models only included transplant recipients who had data available for most of the risk factors in the final model. The nonconditional models used the latest data available at the time of the transplant. In contrast to non-conditional analyses, the conditional analyses also adjusted for post-transplant factors. 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 and corresponding 95% confidence intervals and p-values. Tables and forest plots show hazard ratios and 95% confidence intervals for categoric variables in the final models. A more detailed explanation of the analytical methodology is available online (www.ishlt.org/registries) and in previous annual reports.2–5 This report refers to specific online eSlides when particular data are discussed but not shown due to space limitations; eSlide numbers refer to the online pediatric lung slides. We recommend interpretation of unadjusted analyses and predictive/comparative risk models in the context of the limitations typical of registry data.
Focus theme methods For this report, the Registry Steering Committee selected the focus theme of EGF. The granularity of data collected in the Registry influenced the definition of EGF. We defined EGF as a composite end point of death or retransplant associated with graft failure within the first 30 days after transplant. Death or retransplant events associated with causes we
Pediatric patients Source of graft failure
Reason of graft failure
Death (not EGF) Total Cardiovascular Cardiac arrest Cardiogenic shock Other specify Ventricular failure Cerebrovascular Other specify Stroke Hemorrhage Intraoperative Other specify Post-operative Immunosuppressive drugrelated–hematologic Infection Bacterial septicemia Fungal, other specify Other specify Multiple organ failure Not reported Graft failure Total r 30 daysa Adenoviral pneumonitis Not reported
No. % 36 100.0 3 1 4 2
8.3 2.8 11.1 5.6
1 3
2.8 8.3
1 4 2 1
2.8 11.1 5.6 2.8
3 8.3 1 2.8 2 5.6 7 19.4 1 2.8 4 100.0 1 3
25.0 75.0
EGF, early graft failure. a But not death or retransplant r30 days.
believed were not due to intrinsic graft failure were excluded from the EGF definition. Because our EGF definition required an association between these outcome events and graft failure, rather than all-cause death or allcause retransplant, death or retransplant events that did not meet the EGF criteria occurred in a large number of transplant recipients. In addition, if the center reported the cause for a transplant recipient’s death or retransplant as “unknown,” we counted the recipient as having EGF. If the center did not report a cause for a transplant recipient’s death or retransplant (i.e., field was left blank), we did not count the recipient as having EGF. Of note, the composite end point excluded graft failure that did not lead to death or retransplant within 30 days, although such events were rarely reported. The definition of EGF in this report certainly differs from the definition of primary graft dysfunction in thoracic transplantation and reflects the most severe sub-group of early graft injury resulting in graft loss. For estimating the cumulative incidence of EGF at 30 days and the percentage of transplant recipients that developed EGF within 30 days, we used a competing risks extension of the Kaplan-Meier method. Competing events
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1257 0-10 years
11-17 years
18-34 years
35-49 years
50-59 years
60+ years
100%
% of Donors
80%
60%
40%
20%
0% North America (N=352)
Europe (N=321)
Figure 1 Pediatric lung recipients. Recipient age distribution by year of transplant. Analysis includes deceased and living donor transplants. ISHLT, International Society for Heart and Lung Transplantation.
Other (N=45)
Figure 4 Pediatric lung transplants. Donor age distribution by location (transplants: January 2008—June 2014). The analysis excluded transplants with unknown donor age and living donor transplants.
Cystic Fibrosis
IPAH
IPF
BOS
Other
Congenital heart disease
Retx
100%
% of Transplants
80%
60%
40%
20%
0% Europe (N=311)
Figure 2 Pediatric lung transplants. Number of centers reporting transplants by location.
North America (N=351)
Other (N=52)
Figure 5 Pediatric lung transplants. Diagnosis distribution by location (transplants: January 2008–June 2014). BOS, bronchiolitis obliterans syndrome; IPAH, idiopathic pulmonary artery hypertension; IPF, interstitial pulmonary fibrosis; Retx, retransplant.
100
Induction (N = 209)
Survival (%)
No Induction (N = 92)
75
50 p=0.9444
25
0
0
1
2
3
4
5
Years
Figure 6 Pediatric lung transplants. Kaplan-Meier survival stratified by induction use (transplants: January 2008–June 2013). Figure 3 Pediatric lung transplants. Recipient age distribution by location (transplants: January 2008–June 2014).
consisted of death or retransplant within 30 days posttransplant and not meeting the EGF criteria or graft failure not associated with death or retransplant. We used consistent EGF definitions for the pediatric and adult age groups within each organ (heart and lung). However, causes of death or retransplant that were included in the definition of EGF differed between heart and lung transplant. The causes of death and causes of retransplant leading to death within 30 days of lung transplant are listed in Tables 1 and 2.
Volume, age distribution, indications, and donor characteristics Since 1986, 2,091 pediatric lung transplants and 689 pediatric heart-lung transplants were performed and included in the Registry. In 2013, the last complete year included in this year’s Registry report, the number of pediatric lung transplants increased to 124 compared with 95 in the previous year (Figure 1).6 As in previous years, most lung transplants were done in older children (11–17 years). In 2013, 75% of children who received transplants were aged Z11 years, whereas only 3 lung transplants in infants (o1 year) were performed.
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Table 3
Indications for Pediatric Lung Transplants by Age Group (Transplants: January 2000–June 2014)
Diagnosis Cystic fibrosis IPAH Obliterative bronchiolitis Retransplant No retransplant Congenital heart disease Pulmonary fibrosis Idiopathic Other Retransplant, not obliterative bronchiolitis Interstitial pneumonitis Pulmonary vascular disease Eisenmenger’s syndrome Surfactant protein B deficiency COPD/emphysema Bronchopulmonary dysplasia Bronchiectasis Other
o1 year
1–5 years
6–10 years
11–17 years
No. (%)
No. (%)
No. (%)
No. (%)
0 (0) 7 (13.0)
5 (5.7) 19 (21.8)
99 (50.5) 20 (10.2)
726 (69.1) 83 (7.9)
0 (0) 0 (0) 8 (14.8)
4 (4.6) 8 (9.2) 7 (8.0)
6 (3.1) 21 (10.7) 3 (1.5)
33 (3.1) 48 (4.6) 8 (0.8)
8 15 3 2 2 1 0 0 1 0 12
29 28 24 1 1 4 0 0 6 14 43
4 7 0 0 2 0 11 0 4 0 11
(7.4) (13.0) (0) (0) (3.7) (0) (20.4) (0) (7.4) (0) (20.4)
11 10 4 2 5 1 4 0 2 0 5
(12.6) (11.5) (4.6) (2.3) (5.7) (1.1) (4.6) (0) (2.3) (0) (5.7)
(4.1) (7.7) (1.5) (1.0) (1.0) (0.5) (0) (0) (0.5) (0) (6.1)
(2.8) (2.7) (2.3) (0.1) (0.1) (0.4) (0) (0) (0.6) (1.3) (4.1)
COPD, chronic obstructive pulmonary disease; IPAH, idiopathic pulmonary arterial hypertension.
100 Year 1 (N = 277)
% of patients
80
Year 5 (N = 142)
60
40
20
0 Cyclosporine
Tacrolimus
Sirolimus/ Everolimus
MMF/MPA
Azathioprine
Prednisone
Figure 7 Pediatric lung recipients. Maintenance immunosuppression at the time of follow-up (follow-ups: January 2008–June 2014). The analysis was limited to patients who were alive at the follow-up. MMF/MPA, mycophenolate mofetil/mycophenolic acid.
100% Other
% of Patients
80%
Tacrolimus + Sirolimus/Everolimus Tacrolimus
60% Tacrolimus + MMF/MPA
40%
Tacrolimus + AZA Cyclosporine + MMF/MPA
20%
Cyclosporine + AZA
0%
Year 1 (N = 277)
Year 5 (N = 142)
NOTE: Different patients are analyzed in Year 1 and Year 5.
Figure 8 Pediatric lung recipients. Maintenance immunosuppression drug combinations at the time of follow-up (follow-ups: January 2008–June 2014). The analysis was limited to patients who were alive at the time of the follow-up. AZA, azathioprine; MMF/MPA, mycophenolate mofetil/mycophenolic acid.
Figure 9 Adult and pediatric lung transplants. Kaplan-Meier survival by recipient age group (transplants: January 1990– June 2013).
The age distribution of recipients has remained relatively constant (Figure 1). The number of centers reporting pediatric lung transplants in 2013 increased to 45 from 40 in 2012, with 20 centers located in Europe, 22 centers located in North America, and 3 centers located in other areas (Figure 2). As before, most centers (38 [84%]) conducted 1 to 4 procedures annually, 5 centers performed between 5 to 9 procedures, and 2 centers performed 4 10 procedures (eSlide 13). Fifty percent of the transplants performed occurred in centers that do Z 5 procedures annually. The age distribution of pediatric lung transplants differs by location, with 81% of lung transplants in Europe performed in older children (Z11 years) compared with 67% in North America (Figure 3). Most (58%) of donors are aged o 18 years, with o 10% of the donors aged 4 50 years (Figure 4). The donor age distribution varies considerably between regions: in North America, 76% of donors were pediatric, whereas in Europe
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Figure 10 Pediatric lung transplants. Kaplan-Meier survival by recipient age group (transplants: January 1990–June 2013).
Figure 11 Pediatric lung transplants. Kaplan-Meier survival conditional to recipient survival to 1 year after transplant shown by recipient age group (transplants: January 1990–June 2013). Conditional median survival is defined as median survival limited to patients surviving to 1 year after transplant.
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Figure 14 Pediatric lung transplants. Recipient age and hazard of 1-year mortality/graft failure (January 1996–June 2013).
Figure 15 Pediatric lung transplants. Recipient age and hazard of 5-year mortality/graft failure (transplants: January 1996– June 2009).
Figure 12 Pediatric lung transplants. Kaplan-Meier survival by era (transplants: January 1988–June 2013). Conditional survival is defined as median survival limited to patients surviving to 1 year after transplant.
Figure 16 Pediatric lung transplants. Freedom from bronchiolitis obliterans syndrome (follow-ups: April 1994–June 2014).
Figure 13 Pediatric lung transplants. Kaplan-Meier survival by donor age for recipients aged 11 to 17 years (transplants: January 1990–June 2013).
Figure 17 Pediatric lung transplants. Freedom from bronchiolitis obliterans syndrome by age group (follow-ups: April 1994– June 2014).
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Table 4 Cumulative Morbidity Rates in Pediatric Lung Transplant Survivors Within 1, 5, and 7 Years After Transplant (Follow-ups: April 1994–June 2014)
Outcome a
Hypertension Renal dysfunction Creatinine, mg/dl r2.5 (abnormal) 42.5 Chronic dialysis Renal transplant Hyperlipidemiaa Diabetesa BOS
Within 1 year
Total with known response
Within 5 years
Total with known response
Within 7 years
Total with known response
(%)
(No.)
(%)
(No.)
(%)
(No.)
41.4 9.4
765 795
67.7 29.6
229 247
… 42.8
… 138
781 797 739
23.1 4.0 1.6 0.8 17.7 35.2 35.9
231 250 192
32.6 6.5 0.7 2.9 … … 41.9
… … 93
6.5 1.9 0.8 0.3 5.1 21.3 12.2
BOS, bronchiolitis obliterans syndrome. a Data are not available 7 years post-transplant.
Table 5
Cumulative Post-transplant Malignancy Rates in Pediatric Lung Transplants Survivors (Follow-ups: April 1994–June 2014) 1-year survivors
5-year survivors
7-year survivors
Malignancy and type
No. (%)
No. (%)
No. (%)
No malignancy Malignancy (all types combined) Malignancy typea Lymphoma Other Type not reported
770 (95.1) 40 (4.9)
231 (89.5) 27 (10.5)
132 (91) 13 (9%)
a
38 2 0
26 1 1
13 0 0
Recipients may have experienced 41 type of malignancy, so the sum of individual malignancy types may exceed the total number with a malignancy.
Table 6
Cause of Death in Pediatric Lung Transplant Recipients (Deaths: January 2000–June 2014) 0-30 days (n ¼ 76)
31 days–1 year (n ¼ 120)
41–3 years (n ¼ 182)
43–5 years (n ¼ 100)
45 years (n ¼ 121)
Cause of death
No. (%)
No. (%)
No. (%)
No. (%)
No. (%)
Bronchiolitis Acute rejection Lymphoma Malignancy, non-lymphoma CMV Infection, non-CMV Graft failure Cardiovascular Technical Multiorgan failure Other
0 3 (3.9) 0 0 0 13 (17.1) 10 (13.2) 13 (17.1) 10 (13.2) 13 (17.1) 14 (18.4)
14 2 3 2 2 34 25 6 3 19 10
65 5 3 1 0 25 51 3 3 11 15
39 2 4 0 0 16 24 1 3 4 7
55 0 5 6 0 8 28 1 2 7 9
(11.7) (1.7) (2.5) (1.7) (1.7) (28.3) (20.8) (5.0) (2.5) (15.8) (8.3)
(35.7) (2.7) (1.6) (0.5) (13.7) (28.0) (1.6) (1.6) (6.0) (8.2)
(39.0) (2.0) (4.0)
(16.0) (24.0) (1.0) (3.0) (4.0) (7.0)
(45.5) (4.1) (5.0) (6.6) (23.1) (0.8) (1.7) (5.8) (7.4)
CMV, cytomegalovirus.
and in other centers, 41% and 47%, respectively, were aged o18 years (Figure 4). There have not been significant changes during the past 2 decades in the diagnoses leading to lung transplants in children.3 Most transplant procedures are performed in children with cystic fibrosis (CF) lung disease; in addition,
there are considerable regional differences (Figure 5). In North America, 49% of the pediatric lung transplant recipients have CF compared with 68% in Europe (Figure 5). Further, the distribution of underlying diagnoses in pediatric lung transplant recipients depends on their age group. In children aged Z 11 years, 69% have CF compared
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with 51% in younger children aged 6 to 10 years (Table 3). In recipients aged o 1 year, the combined forms of pulmonary fibrosis, surfactant protein B deficiency, congenital heart disease, and idiopathic pulmonary arterial hypertension were the 4 most frequent diagnoses leading to lung transplantation (Table 3).
Immunosuppressive therapy Induction The use of induction immunosuppression in pediatric lung transplantation is similar to last year’s report.3 Most children (68%) received induction treatment, of which 54% were treated with an interleukin-2 receptor antagonist (eSlide 35). A similar proportion of pediatric heart transplant recipients received induction therapy (68%); however, only 24% received induction with an interleukin-2 receptor antagonist, and 48% received anti-thymocyte globulin.7 There was no significant survival benefit for pediatric lung transplant recipients who received induction (Figure 6).
Maintenance A triple-maintenance immunosuppressive treatment including a calcineurin inhibitor, cell-cycle inhibitor, and prednisone was the most common maintenance immunosuppression regimen for children after lung transplantation. Tacrolimus is prescribed in 97% of children in the first year after transplant in (Figure 7). Mycophenolate mofetil/mycophenolic acid was the first choice of cell-cycle inhibitor, used in 82% of patients at 1 year after transplantation, with 78% of all patients receiving it in combination with tacrolimus. At the 5-year follow-up, 61% of children were receiving tacrolimus and mycophenolate mofetil/mycophenolic acid as maintenance (Figure 8). The number of pediatric recipients receiving a combination of tacrolimus and sirolimus/everolimus at 5 years post-transplant is low, at 4% (Figure 8). More than 90% of children received prednisone at 5 years post-transplant.
Outcomes of primary transplants Survival Survival in children after lung transplantation was similar to that reported in adults, with a median survival of 5.3 vs 5.6 years, respectively, for patients who received transplants between January 1990 and June 2013 (Figure 9). There was a significantly superior survival after bilateral/ double pediatric lung transplants (n ¼ 1,762) compared with single-lung transplants (n ¼ 88), with a median unadjusted survival of 5.6 vs 2.2 years, respectively (eSlide 22). No statistical difference existed between overall survival of CF recipients and non-CF recipients (eSlide 23). Although overall survival and survival conditional to recipient survival to 1 year after transplant was numerically lower in children aged Z 11 years, this difference was not statistically significant (Figures 10 and 11). There was a
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statistically significant improvement in survival comparing the most recent eras (since 2000) with the earlier transplant era of 1988 to 1999, but survival did not improve significantly when the 2 most recent eras—2000 to 2007 vs. 2008 to June 2013—were compared (Figure 12). Although survival of recipients aged 11 to 17 years appears inferior if older donors (Z 50 years) were used, pair-wise comparisons were not significantly different (p o 0.05; Figure 13).
Functional status Overall functional status of children after lung transplantation remained good as reported by the physician. More than 80% of surviving children followed up between January 2008 and June 2014 had a functional status of Z80% Lansky score through 3 years post-transplant (eSlide 31).
Complications and morbidities At 1-year post-transplant (follow-ups: April 1994–June 2014), hypertension was the most common morbidity in 440% of surviving children, followed by diabetes mellitus in 21% and bronchiolitis obliterans syndrome (BOS) in 12% (Table 4). Hypertension was reported in approximately 68% of children within 5 years post-transplant. Other frequent morbidities within 5 years post-transplant were diabetes mellitus (35%), BOS (36%), and chronic kidney dysfunction (30%). Additional details of the cumulative prevalence of morbidities are reported in Table 4. At 5 years posttransplant, 90% of surviving transplant recipients had no malignancies. Almost all malignancies in pediatric lung transplant recipients within 5 years of transplant were lymphomas (Table 5). Unlike adult lung transplant recipients, pediatric transplant recipients rarely develop skin cancer.2 Significant categoric risk factors for 1-year mortality or graft failure were pre-transplant ventilator use, retransplantation, earlier era of transplantation, and cytomegalovirus high-risk donor/recipient mismatch (eSlide 60). Significant categoric risk factors for 5-year mortality or graft failure included retransplantation and earlier era of transplantation (eSlide 63). These risk factors were also similar to mortality risk factors seen in the adult lung transplant recipients.2 The hazard of 1-year post-transplant mortality with regard to recipient age was fairly linear throughout the pediatric recipient age range, with higher age representing higher risk (Figure 14). The association of recipient age with 5-year post-transplant survival was also significant; however, the association had a U-shaped appearance (Figure 15).
Bronchiolitis obliterans syndrome BOS, the most common form of chronic lung allograft dysfunction, is the most frequent overall cause of morbidity, with a prevalence of 450% of surviving transplant recipients by 5 years post-transplant (Figure 16). Though BOS appeared to be more common in 11- to 17-year-olds, with 60% affected by 5 years post-transplant, no pair-wise
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Figure 18 Pediatric lung transplants. Cumulative incidence of early graft failure (EGF) by transplant type (transplants: January 2005–December 2013).
Figure 19 Pediatric lung transplants. Percentage with early graft failure (EGF) by EGF type and year for primary transplants (primary transplants: January 2005–December 2013).
Figure 20 Pediatric lung transplants. Cumulative incidence of early graft failure (EGF) by diagnosis and era (primary transplants: January 2005–December 2013). CF, cystic fibrosis.
10% Death
% of transplants with EGF
9%
Retransplant
8% 7%
No pair-wise comparisons of % with EGF significant at p < 0.05.
6% 5% 4%
Figure 22 Pediatric lung transplants. Cumulative incidence of early graft failure (EGF) by donor age group (transplants: January 2005–December 2013).
Figure 23 Pediatric lung transplants. Cumulative incidence of early graft failure (EGF) by gender (primary transplants: January 2005–December 2013).
Figure 24 Pediatric lung transplants. Percentage of recipients with early graft failure (EGF) by EGF type and center volume (primary transplants: January 2005–December 2013).
comparisons were significant (Figure 17). There was a significant statistical difference with regard to freedom from BOS in surviving CF recipients compared with recipients with idiopathic pulmonary hypertension, with 44% vs 56% freedom from BOS at 5 years, respectively (p ¼ 0.043; eSlide 48).
3% 2%
Causes of death
1% 0% 0-5 years (N=126)
6-10 years (N=702)
11-17 years (N=102)
Figure 21 Pediatric lung transplants. Percentage of recipients with early graft failure (EGF) by EGF type and age group (primary transplants: January 2005–December 2013).
The most common causes of deaths that occurred in the era January 2000 to June 2014 within the first 30 days after transplantation were cardiovascular and multiorgan failure, representing 34% of all cases (Table 6). Up to 1 year after
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transplant, non-cytomegalovirus infection was the leading cause of death in 24%.5,6 Beyond the first year after transplant, BOS and graft failure are by far the major causes of death: BOS represented 39% and 45% of deaths between 3 and 5 years and at 4 5 years, respectively, and graft failure represented 24% and 23% of deaths at 3 to 5 years and at 4 5 years, respectively (Table 6).
Disclosure statement
Early graft failure
References
This Registry report focuses on an overall theme of EGF. The incidence of EGF in primary transplants during the first 30 days after transplant was between 1% and 2% of recipients. The incidence of EGF for retransplant recipients was significantly greater, reaching 9% at 30 days after transplant (Figure 18). The number of recipients per year with EGF has remained fairly constant during the past 9 years, ranging from 0 to 4 occurrences per year (Figure 19). Further, during this same interval, there has been no significant era effect or difference between CF and non-CF transplant recipients in the incidence of EGF (Figure 20) and no significant difference in EGF rates between age groups (Figure 21), donor age groups (Figure 22), recipient gender (Figure 23), or center volume (Figure 24). In conclusion, the 2015 ISHLT Registry Report on Pediatric Lung Transplantation shows further improvements in survival in children undergoing lung transplantation, with results of lung transplantation in children comparable with results seen in adult recipients. To date, however, BOS continues to be the most important obstacle for better longterm outcomes across all age groups. The incidence of EGF has been 1% to 4% during the past 9 years. We identified retransplant as the strongest risk factor for EGF after pediatric lung transplantation. No clear associations with other donor or recipient characteristics were apparent.
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. Yusen RD, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart-lung transplant report—2014; focus theme: retransplantation. J Heart Lung Transplant 2014;33:1009-24. 3. Lund LH, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-first official adult heart transplant report—2014; focus theme: retransplantation. J Heart Lung Transplant 2014;33:996-1008. 4. Dipchand AI, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: seventeenth official pediatric heart transplantation report—2014; focus theme: retransplantation. J Heart Lung Transplant 2014;33:985-95. 5. Benden C, Goldfarb SB, Edwards LB, et al. The registry of the International Society for Heart and Lung Transplantation: seventeenth official pediatric lung and heart-lung transplantation report—2014; focus theme: retransplantation. J Heart Lung Transplant 2014;33: 1025-33. 6. 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; focus theme: age. J Heart Lung Transplant 2013;32:989-97. 7. Dipchand A, Rossano JW, Edwards LB, et al. The Registry of the International Society for Heart and Lung Transplantation: Eighteenth Official Pediatric Heart Transplantation Report — 2015; Focus Theme: Early Graft Failure. J Heart Lung Transplant 2015;34:1233-43.
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.