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The Registry of the International Society for Heart and Lung Transplantation: Thirty-third Adult Lung and Heart–Lung Transplant Report—2016; Focus Theme: Primary Diagnostic Indications for Transplant
Reprint requests: Josef Stehlik, MD, MPH, University of Utah Health Sciences Center, Division of Cardiovascular Medicine, 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
This Thirty-third Adult Lung and Heart–Lung Transplant Report summarizes data from 55,795 adult lung and 3,879 adult heart–lung transplants performed through June 30, 2015 and reported to the Registry. In addition to reporting key data for donor and recipient characteristics, transplant events and recipient treatments and outcomes, this year’s report focuses on an overall theme of primary diagnostic indications for transplant. We present data on the distribution of diagnostic categories (see Figure 1), demographics of patients with the different lung disorders leading to the need for transplant, associations of the diagnoses with outcomes, and other data of interest related to this topic. The Registry’s online slide sets show results from additional analyses and complementary information not included in this publication (see http://ishlt.org/registries/slides.asp?slides=heartLungRegistry/).
Figure 1Number of adult lung transplants for major primary diagnostic indication and year of transplantation (transplants: 1990 to 2014). CF, cystic fibrosis–associated bronchiectasis; IIP, idiopathic interstitial pneumonia; ILD, interstitial lung disease; COPD without A1ATD, chronic obstructive pulmonary disease (COPD) without α1-antitrypsin deficiency (A1ATD).
Data collection, conventions and statistical methods
National and multinational organ/data exchange organizations and individual centers submit data to the ISHLT Registry. Since the Registry’s inception, 457 heart transplant centers,
The Registry of the International Society for Heart and Lung Transplantation: thirty-third official adult heart transplantation report—2016; Focus theme: Primary diagnostic indications for transplant.
The Registry of the International Society for Heart and Lung Transplantation: nineteenth official pediatric heart transplantation report—2016; Focus theme: Primary diagnostic indications for transplant.
The Registry of the International society for Heart and Lung Transplantation: nineteenth official pediatric lung and heart–lung transplantation report—2016; Focus theme: Primary diagnostic indications for transplant.
and 177 heart–lung transplant centers have reported data to the Registry. In our estimation, data submission to the Registry represents approximately two thirds of the worldwide thoracic transplant activity.
This report presents an overview of donor and recipient characteristics and outcomes. Additional and extended analyses are presented in the aforementioned online slide sets (5 separate slide sets supplement the report data, including: “Introduction”; “Overall Lung Transplant”; “Overall Heart–Lung Transplant”; “Adult Lung Transplant”; and “Adult Heart–Lung Transplant”). The ISHLT website also contains slide sets for previous annual reports. This article refers to specific online eSlides when particular data are discussed but not presented due to space limitations; eSlide numbers refer to the online Adult Lung Transplant slides (e.g., eSlide LU 3) or Adult Heart–Lung Transplant slides (e.g., eSlide HL 3), unless otherwise specified.
The Registry website also provides spreadsheets of the data elements collected in the Registry. 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.
Analytical conventions
Unless otherwise specified, analyses of lung transplants do not include heart–lung transplants. Retransplant includes those with a previously reported transplant of the same organ type, a same organ type in combination, or a retransplant diagnosis. Incomplete identification of all transplants for an individual may lead to underestimation of the number of retransplant events.
The Registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart–lung transplant report—2014; Focus theme: retransplantation.
When considered appropriate, we report separate or combined lung primary transplants and retransplants.
The Registry does not capture the exact occurrence date for most secondary outcomes (e.g., renal dysfunction), but it does capture the window of occurrence (i.e., the event occurred between the first and the second year annual follow-up visits). For the annual report, we use the midpoint between annual follow-ups as a surrogate for the event date.
There is some bias in reporting secondary outcomes and other information on the follow-up when a death is reported. To reduce the possibility of underestimating event rates or other outcomes, we limit some analyses to surviving patients.
For time-to-event rates and cumulative morbidity rates, we censored follow-up of transplant recipients who did not experience the event of interest at the last time the recipient was reported not to have had the event, either the most recent annual follow-up or the time of retransplantation. We truncated time-to-event graphs (e.g., survival graphs) when the number of individuals at risk reached <10. Additional information regarding the general statistical methods used for analyses and data interpretation is included in the Supplementary material (available online at www.jhltonline.org).
Focus theme methods: Primary diagnostic indications for transplant
The Registry Steering Committee selected underlying organ failure diagnosis (i.e., primary disease indication for transplant) as the theme topic for the 2016 report. The Steering Committee reviewed all diagnoses and categorized them by organ (i.e., heart or lung) and age group (i.e., adult or pediatric). The listing of diagnoses in each category includes all diagnoses available for collection, although some categories do not have transplants reported. Table 1 presents a detailed categorization of the diagnoses for adult lung transplants. Of note, some diagnostic misclassification could have occurred due to choice of primary diagnosis (e.g., obliterative bronchiolitis [OB] due to rheumatoid arthritis [RA] could have been classified as OB or connective tissue disease [CTD] associated with rheumatoid disease).
Table 1Categorization of Primary Diagnostic Indications for Adult Lung Transplants
Category (abbreviation) for Registry Report
Diagnoses in category used for reporting to Registry
Chronic obstructive pulmonary disease (COPD) with α1-anti-trypsin deficiency (A1ATD)
•
α1-antitrypsin deficiency
Bronchiectasis not associated with cystic fibrosis (CF) (non-CF bronchiectasis)
•
Bronchiectasis
•
Common variable immune deficiency
•
Hypogammaglobulinemia
•
Kartagener׳s syndrome
•
Primary ciliary dyskinesia
Cancer
•
Bronchoalveolar carcinoma
•
Cancer
•
Carcinoid tumorlets
Bronchiectasis associated with CF
•
CF
COPD without A1ATD
•
COPD/emphysema
Connective tissue disease (CTD)
•
Collagen vascular diseases
•
CTD
•
Lupus
•
Mixed CTD
•
Polymyositis
•
Rheumatoid disease
•
Sjogren’s syndrome
Idiopathic interstitial pneumonia (IIP)
•
Acute interstitial pneumonia
•
Bronchiolitis obliterans and organizing pneumonia (BOOP)/cryptogenic organizing pneumonia (COP)
The Registry now contains data from 55,795 adult lung transplants performed through June 2015. Of these, 53,522 (95.9%) had a primary lung transplantation and 2,273 (4.1%) had a lung retransplant. Data were submitted from 134 participating transplant centers for a total of 3,973 adult lung transplantation procedures performed in 2014 (eSlide LU 4). Figure 1 shows the number of reported adult lung transplants by year for the major primary diagnostic categories, and Table A (see Supplementary material online) provides detailed information on the number of transplants performed for each individual diagnostic category. Figure 2 shows the total number of transplants stratified by procedure type. The trend over the past 3 decades has shown a significant increase in the number of transplants, partly due to new transplant centers participating in the Registry, and the main increase has occurred as bilateral procedures. The number of adult lung transplants reported in 2014 was about 37 times greater than the number of pediatric lung transplants (eSlide Overall Lung Transplant 6).
The Registry of the International society for Heart and Lung Transplantation: nineteenth official pediatric lung and heart–lung transplantation report—2016; Focus theme: Primary diagnostic indications for transplant.
A total of 163 centers reported at least 1 adult lung transplant performed between January 2009 and June 2015 (eSlide LU 7). During this period, almost two thirds of the transplant procedures were performed at 46 centers (28% of centers) that had an average activity of ≥30 transplants per year. Sixteen centers (10% of centers) had an average activity of ≥50 transplants per year and performed 35% of procedures reported during this period. Fifty centers (31% of centers) averaged <10 transplants per year and conducted just under 4% of the procedures.
Indications and other recipient characteristics
Table 2 shows the primary diagnostic indications for lung transplant, stratified by procedure type, and associated counts/proportions of patients transplanted for each indication during the past 2 decades. The most common primary indications consisted of chronic obstructive pulmonary disease without α1-antitrypsin deficiency (COPD without A1ATD; 31%), which, when combined with α1-antitrypsin deficiency (COPD with A1ATD; 5%), totaled more than one third of all transplants. The second most common indication consisted of the broad category of interstitial lung disease (ILD) or pulmonary fibrosis (30%), mainly consisting of idiopathic interstitial pneumonia
An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
(IIP; 24%) and non-IIP ILD (ILD-not IIP, 5%). The third most common indication consisted of bronchiectasis, mainly consisting of cystic fibrosis (CF; 16%), presumably associated with bronchiectasis, whereas non-CF bronchiectasis (2.7%) comprised a much smaller proportion of transplants. Idiopathic pulmonary arterial hypertension
(IPAH; 2.9%) also represented a small proportion, as did non-IPAH PH (1.6%), the latter having about one third of transplants due to scleroderma/CREST and another third due to secondary PH in the last decade. Sarcoidosis had a transplant proportion similar to that of non-CF bronchiectasis and IPAH. About 1% of transplants occurred due to each of any CTD, lymphangioleiomyomatosis (LAM)/tuberous sclerosis, and OB not associated with a previous lung transplant.
Table 2Primary Indications for Adult Lung Transplants (Transplants: January 1995 to June 2015)
Diagnostic groupings based on reporting classification categories; recipients may have secondary diagnoses that overlap with other categories (e.g., sarcoidosis with ILD and PAH). Diagnostic misclassifications may have occurred.
a Diagnostic groupings based on reporting classification categories; recipients may have secondary diagnoses that overlap with other categories (e.g., sarcoidosis with ILD and PAH). Diagnostic misclassifications may have occurred.
b Categories may include other types of idiopathic and non-idiopathic interstitial pneumonia.
An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
The Registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart–lung transplant report—2014; Focus theme: retransplantation.
Of the 55,795 reported adult lung transplants that were performed through June 2015, 2,187 (3.9%) had a first retransplantation and 86 (0.2%) had a second retransplantation. Overall, the annual proportion of reported adult lung retransplants has hovered around 4% or 5% since 2005 (Figure 3; eSlide LU 5). Just under 10% of lung retransplants occurred within the first month after previous lung or heart–lung transplant. The majority of the lung retransplants occurred between 1 and 10 years, and about 6% occurred beyond 10 years after the previous transplant (eSlide LU 6).
Figure 3Number of adult lung retransplants and percent of all adult lung transplants by year and by center geographic location (retransplants: 1990 to 2014; Europe [N = 945], North America [N = 1,125] and other [N = 108]).
For the 53,890 lung transplants that occurred in 1990 through 2014 (Figure 2; eSlide LU 4), recipients who had COPD without A1ATD, IIP and CF contributed the most to the growth in the number of transplants (Figure 1; eSlide LU 13). However, for the more recent period of 1999 through 2014, the percentage of recipients with COPD without A1ATD gradually decreased from 40% to <30%, whereas the percentage of transplants for IIP increased from 16% to 33% (eSlide LU 12). For the most recent decade of reporting, geographic location of transplant centers showed differences as far as indications for lung transplantation. North American centers, in comparison to European centers, had a smaller proportion of recipients transplanted for CF and a larger proportion transplanted for IIP (eSlide LU 14). The most commonly reported (Table 2) indication for adult lung retransplants in January 1995 through June 2015 was bronchiolitis obliterans syndrome (BOS)/OB (eSlide LU 141).
Across all of the major diagnosis groupings, IIP had the highest proportion of recipients >65 years old, and CF had the highest proportion of recipients 18 to 34 years old (eSlide LU 144). IIP was the most common diagnosis in males and COPD was the most common in females (eSlide LU 145).
Immunosuppression
Among the adults who underwent lung transplantation between January 2004 and June 2015, received post-transplant prednisone, and survived to hospital discharge (N = 10,013 with known induction status), 57% received induction therapy (eSlide LU 48). About three fourths of these patients received an interleukin-2 (IL-2) antagonist for induction, whereas just under 15% received polyclonal anti-lymphocyte globulin/anti-thymocyte globulin and just under 12% received alemtuzumab. Interestingly, the use of induction therapy has increased over the last decade, with 70% of adult lung transplant recipients in the first half of 2015 receiving such therapy (Figure 4, eSlide LU 49). Close to 90% of patients in this recent cohort who received induction therapy received an IL-2 antagonist. For adult lung transplant recipients who received post-transplant prednisone and survived to hospital discharge, maintenance immunosuppression that consisted of tacrolimus plus mycophenolate mofetil/mycophenolic acid (MMF/MPA) was the most common regimen at 1 year and at 5 years post-transplant (eSlide LU 57).
Figure 4Adult lung transplant induction immunosuppression by era (transplants: 2004, 2009 and first half of 2015). Analyses are limited to patients surviving to hospital discharge and receiving prednisone.
Adults who underwent primary lung transplantation between January 1990 and June 2014 (N = 49,453) had a median survival of 5.8 years (Figure 5; eSlide LU 20), with unadjusted survival rates of 89% at 3 months, 80% at 1 year, 65% at 3 years, 54% at 5 years and 32% at 10 years. The recipients who survived to 1 year after primary transplant had a conditional median survival of 8.0 years.
Figure 5Adult lung transplant recipient Kaplan-Meier survival by transplant type (transplants: January 1990 to June 2014). Conditional median survival is the time to 50% survival for the subset of recipients alive at 1 year after transplantation.
Survival varied by indication for transplantation (Figure 6; eSlide LU 26). Of the 5 more common indications, lung recipients transplanted for COPD without A1ATD or CF had an unadjusted mortality at 3 months after transplant of around 8% or 9%, whereas those transplanted for IIP, ILD-not IIP and COPD with A1ATD had a mortality rate of approximately 11% to 12%. Within the ILD category, the 6 ILD subtypes resulted in similar post-transplant survival (Figure 7A; eSlide LU 148). Within the PH category, PAH associated with congenital heart disease (PAH-CHD) had lower post-transplant survival in comparison to IPAH and PAH-CTD (Figure 7B; eSlide LU 149). In the bronchiectasis groups, those with CF had better unadjusted survival than those without CF (Figure 7C; eSlide LU 26). For adults who had a primary lung transplant during the same era who survived to 1 year, conditional median survival was higher for CF (11.7 years), as compared to those with A1ATD (8.9 years), ILD-not IIP (8.0 years), COPD (7.1 years) and IIP (7.0 years) (eSlide LU 28).
Figure 6Adult lung transplant recipient Kaplan-Meier survival by primary diagnostic indication for lung transplantation (transplants: January 1990 to June 2014). COPD with A1ATD, α1-anti-trypsin deficiency (A1ATD) associated with chronic obstructive pulmonary disease (COPD); CF, cystic fibrosis–associated bronchiectasis; COPD, without A1ATD; IIP, idiopathic interstitial pneumonia; ILD, interstitial lung disease.
Adults who underwent a first lung retransplantation in the era of January 1990 through June 2014 (N = 1,998) had a very high early mortality and a subsequent median survival of 2.8 years (Figure 5; eSlide LU 20), with unadjusted survival rates of 79% at 3 months, 66% at 1 year, 49% at 3 years, 39% at 5 years and 21% at 10 years. Recipients who survived to 1 year after first retransplant had a conditional median survival of 6.5 years. Patients undergoing a first retransplantation had a significantly lower survival than those undergoing a primary lung transplantation.
Survival after adult lung transplant has changed over time, with the more recent eras showing better survival for primary transplants than the first era. The survival curves separate in the early period after transplant (eSlide LU 22). Survival of adult primary lung transplant recipients was statistically significantly better for females than for males (eSlide LU 25), but this difference may not be clinically relevant.
Causes of death
The major reported causes of mortality (January 1990 through June 2015) within the first 30 days after transplantation consisted of graft failure and non-CMV infections (Table 3). Other significant contributors to early post-transplant death included multiple-organ failure and cardiovascular and technical (i.e., related to the transplant procedure) causes. Last year’s Registry Report provided more detailed analyses related to early graft failure, which included early deaths.
The Registry of the International Society for Heart and Lung Transplantation: thirty-second adult lung and heart–lung transplant report—2015; Focus theme: early graft failure.
During the remainder of the first post-transplant year, non-CMV infection became the most prominent cause of death (eSlide LU 84). After the first post-transplant year, OB/BOS, graft failure and non-CMV infection caused the most deaths. Especially after the first post-transplant year, malignancy became an important contributor to mortality. Long-term (>10 years) known causes of death primarily consisted of OB/BOS and graft failure, non-CMV infection and malignancy (Table 4).
Table 3Known Causes of Death Within 0 to 30 Days for Adult Lung Transplant Recipients, Stratified by Diagnoses (Deaths: January 1990 to June 2015)
Some misclassification may occur among the cause of death terms of bronchiolitis, and acute rejection, and graft failure. Due to variation in reporting, graft failure may represent acute rejection, primary graft dysfunction (PGD) or other causes of death early post-transplant, or BOS or OB or other causes of death late post-transplant.
This column includes deaths for diagnoses shown or not shown in this table, and for unknown diagnosis.
(N = 3,424)
OB/BOS
1 (0.1%)
0
1 (0.1%)
1 (0.7%)
1 (0.3%)
0
10 (0.3%)
Graft failure
183 (25.2%)
38 (21.0%)
188 (22.4%)
45 (30.0%)
64 (16.6%)
78 (30.7%)
838 (24.5%)
Acute rejection
31 (4.3%)
5 (2.8%)
34 (4.1%)
0
7 (1.8%)
9 (3.5%)
113 (3.3%)
Infection, non-CMV
142 (19.6%)
37 (20.4%)
151 (18.0%)
18 (12.0%)
110 (28.6%)
36 (14.2%)
655 (19.1%)
CMV
1 (0.1%)
0
1 (0.1%)
0
0
0
3 (0.1%)
Malignancy, non-lymphoma
0
0
4 (0.5%)
1 (0.7%)
0
0
5 (0.1%)
Lymphoma
1 (0.1%)
0
0
0
0
0
1 (0.0%)
Cardiovascular
92 (12.7%)
28 (15.5%)
107 (12.8%)
22 (14.7%)
28 (7.3%)
33 (13.0%)
397 (11.6%)
Technical
82 (11.3%)
18 (9.9%)
80 (9.5%)
14 (9.3%)
48 (12.5%)
17 (6.7%)
390 (11.4%)
Multiple-organ failure
66 (9.1%)
17 (9.4%)
121 (14.4%)
18 (12.0%)
51 (13.2%)
39 (15.4%)
420 (12.3%)
Other
126 (17.4%)
38 (21.0%)
151 (18.0%)
31 (20.7%)
76 (19.7%)
42 (16.5%)
592 (17.3%)
Data expressed as number (percentage of deaths out of all deaths with known cause in the respective time period). A1ATD, α1-antitrypsin deficiency; BOS, bronchiolitis obliterans syndrome; CF, cystic fibrosis; CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; IIP, idiopathic interstitial pneumonia; ILD-not IIP, interstitial lung disease, but not IIP; IPAH, idiopathic pulmonary arterial hypertension; OB, obliterative bronchiolitis.
a Some misclassification may occur among the cause of death terms of bronchiolitis, and acute rejection, and graft failure. Due to variation in reporting, graft failure may represent acute rejection, primary graft dysfunction (PGD) or other causes of death early post-transplant, or BOS or OB or other causes of death late post-transplant.
b This column includes deaths for diagnoses shown or not shown in this table, and for unknown diagnosis.
Some misclassification may occur among the cause of death terms of bronchiolitis, and acute rejection, and graft failure; Due to variation in reporting, graft failure may represent acute rejection, primary graft dysfunction or other causes of death early post-transplant, or BOS, OB or other causes of death late post-transplant.
This column includes deaths for diagnoses shown or not shown in this table, and for unknown diagnosis.
(N = 1,551)
OB/BOS
133 (22.3%)
49 (23.0%)
31 (16.8%)
4 (14.3%)
34 (18.5%)
13 (21.7%)
333 (21.5%)
Graft failure
92 (15.4%)
31 (14.6%)
31 (16.8%)
3 (10.7%)
29 (15.8%)
14 (23.3%)
241 (15.5%)
Acute rejection
1 (0.2%)
0
0
0
0
0
3 (0.2%)
Infection, non-CMV
101 (16.9%)
42 (19.7%)
24 (13.0%)
4 (14.3%)
29 (15.8%)
3 (5.0%)
256 (16.5%)
CMV
0
0
1 (0.5%)
0
0
0
1 (0.1%)
Malignancy, non-lymphoma
71 (11.9%)
29 (13.6%)
42 (22.7%)
5 (17.9%)
26 (14.1%)
9 (15.0%)
212 (13.7%)
Lymphoma
8 (1.3%)
5 (2.3%)
5 (2.7%)
2 (7.1%)
18 (9.8%)
2 (3.3%)
47 (3.0%)
Cardiovascular
52 (8.7%)
15 (7.0%)
12 (6.5%)
3 (10.7%)
4 (2.2%)
5 (8.3%)
111 (7.2%)
Technical
4 (0.7%)
1 (0.5%)
1 (0.5%)
0
0
0
10 (0.6%)
Multiple-organ failure
38 (6.4%)
9 (4.2%)
7 (3.8%)
1 (3.6%)
11 (6.0%)
5 (8.3%)
87 (5.6%)
Other
96 (16.1%)
32 (15.0%)
31 (16.8%)
6 (21.4%)
33 (17.9%)
9 (15.0%)
250 (16.1%)
Data expressed as number (percentage of deaths out of all deaths with known cause in the respective time period). Refer to Table 1 for abbreviations.
a Some misclassification may occur among the cause of death terms of bronchiolitis, and acute rejection, and graft failure; Due to variation in reporting, graft failure may represent acute rejection, primary graft dysfunction or other causes of death early post-transplant, or BOS, OB or other causes of death late post-transplant.
b This column includes deaths for diagnoses shown or not shown in this table, and for unknown diagnosis.
Lung retransplant recipients (eSlide LU 86) had similar trends of major reported causes of mortality (1990 to June 2015) to those seen with primary lung transplant recipients. However, lung retransplant recipients had a slightly higher proportion of deaths due to the combination of OB/BOS and graft failure than seen in primary lung transplant recipients.
Among the more common diagnostic indications for adult lung transplant, some differences (not adjusted for other factors) in known causes of death stand out (Table 3, Table 4). Those transplanted for CF had a higher proportion of deaths associated with infection and a lower proportion of deaths associated graft failure within the first 30 days after transplant. For long-term (>10 years) known causes of death, those transplanted for CF had a relatively lower proportion of deaths associated with cardiovascular causes, and relatively higher proportion associated with lymphoma. Those with ILD-not IIP had a relatively low proportion of graft failure associated with long-term death, whereas those with IPAH had a relatively high proportion.
Risk factors for mortality
For 36,809 adult lung transplants performed between January 2002 and June 2014, categorical risk factors significantly associated with mortality during first post-transplant year in multivariable analyses included recipient male gender, type of underlying lung disease, pre-transplant long-term steroid use, retransplantation,
The Registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart–lung transplant report—2014; Focus theme: retransplantation.
earlier era of transplant, increased severity of recipient illness at the time of transplantation (i.e., intensive care unit, ventilator, dialysis), donor cause of death other than anoxia, cerebrovascular/stroke or head trauma, higher mismatching of donor and recipient HLA type, cytomegalovirus (CMV) mismatch (donor CMV+ and recipient CMV–) and non-identical donor and recipient blood groups (Figure 8; eSlide LU 90). Continuous risk factors significantly associated with mortality included older recipient (Figure 9A; eSlide 92) and donor age at transplant, lower transplant center volume (Figure 9B; eSlide 100), shorter donor height, extremes of donor height minus recipient height difference, lower donor-to-recipient body mass index (BMI) ratio, higher pre-transplant bilirubin, higher amount of supplemental oxygen required at rest, lower percent predicted value of the forced vital capacity (FVC) and higher creatinine (eSlides LU 91 to 101). The increased risk of 1-year post-transplant mortality with older recipient age began at approximately 55 years and rose thereafter (Figure 9A; eSlide 92).
Figure 8Adult lung transplant recipient categorical risk factors for mortality within the first post-transplant year (transplants: January 2002 to June 2014). ABO refers to blood type matching of donor and recipient; CF, cystic fibrosis–associated bronchiectasis; CMV, cytomegalovirus; COPD without A1ATD, chronic obstructive pulmonary disease (COPD) without α1-antitrypsin deficiency (A1ATD); HLA mm, human leukocyte antigen mismatch; ILD, interstitial lung disease; ICU, intensive care unit; IIP, idiopathic interstitial pneumonia; IPAH, idiopathic pulmonary arterial hypertension; PH, pulmonary hypertension. **Other includes all diagnoses other than CF, COPD without A1ATD, COPD with A1ATD, ILD-not IIP, non-CF bronchiectasis, IPAH, sarcoidosis, retransplant, lymphangioleiomyomatosis (LAM)/tuberous sclerosis, IIP, PH-not IPAH, OB and CTD.
Figure 9Hazard ratio for mortality within the first post-transplant year for adult lung transplant recipient age and center volume (transplants: January 2001 to June 2014). Dashed lines represent 95% confidence intervals. (A) Recipient age (years). (B) Center volume.
For lung transplants performed between January 2002 and June 2010 (N = 21,659), pre- and peri-transplant risk factors for 5-year post-transplant mortality (Figure 10; eSlide LU 114) showed some overlap with risk factors for 1-year post-transplant mortality (Figure 8; eSlide LU 90). Categorical risk factors that showed an independent association with risk of death during the first 5 years post-transplant similarly included recipient type of underlying lung disease. Those who had LAM/tuberous sclerosis or CF had a lower risk of mortality compared with a reference COPD-without-A1ATD group, whereas those retransplanted had a higher risk. Additional risk factors included history of pulmonary embolism, earlier era of transplant, increased severity of recipient illness at the time of transplantation (i.e., intensive care unit), allograft rejection in first year after transplant, donor history of diabetes and donor–recipient CMV mismatch. Statistically significant continuous risk factors (Table 5) included lower transplant center volume, lower donor-to-recipient BMI ratio and recipient factors of older age at transplant and higher levels of supplemental oxygen required at rest (eSlides LU 115 to 121).
Figure 10Adult lung transplant recipient categorical risk factors for mortality within the first 5 post-transplant years (transplants: January 2002 – June 2010). LAM, lymphangioleiomyomatosis; COPD without A1ATD, chronic obstructive pulmonary disease not associated with α1-antitrypsin deficiency (A1ATD); CF, cystic fibrosis–associated bronchiectasis; CMV, cytomegalovirus; ICU, intensive care unit.
Risk factors for 5-year mortality, conditional on survival to 1-year (N = 28,286; Figure 11; eSlide LU 122), showed some differences in the effect of the indication for lung transplant, compared with the 1-year (Figure 8; eSlide LU 90) and 5-year (Figure 10; eSlide LU 114) non-conditional models. Recipients with BOS (the highest hazard ratio) or rejection in the first post-transplant year had a higher risk of mortality at 5 years. Statistically significant continuous risk factors (Table 5) included lower ratio of donor-to-recipient BMI, and extremes of recipient age at transplant (eSlides LU 123 to 126). Similar to the non-conditional 1- and 5-year mortality risk models, the conditional 5-year mortality risk model found a negative impact on longer term survival for advanced recipient age and lower transplant center volume. The latter finding suggests that programmatic differences associated with transplant volume exist beyond those related to the transplant procedure.
Figure 11Adult lung transplant recipient categorical risk factors for mortality within the first 5 post-transplant years, conditional on survival in the first year (transplants: January 2002 to June 2010). LAM, lymphangioleiomyomatosis; COPD without A1ATD, chronic obstructive pulmonary disease not associated with α1-antitrypsin deficiency (A1ATD); CF, cystic fibrosis–associated bronchiectasis; COPD with A1ATD, A1ATD associated with COPD; HTN, systemic hypertension; ICU, intensive care unit; CMV, cytomegalovirus; OB, obliterative bronchiolitis.
For adult lung transplants performed between January 1998 and June 2004, the 10-year post-transplant mortality model (eSlide LU 127 to 136; Table 5) included some of the same risk factors that the 1-year (Figure 8, Figure 9; eSlides LU 90, 92 and 100), 5-year (Figure 10; eSlide LU 114) and 5-year conditional (Figure 11; eSlide LU 122) post-transplant mortality models included.
Specifically related to the report theme of diagnostic indication for transplant, many diagnoses (e.g., ILD-not IIP, sarcoidosis, non-CF bronchiectasis, PH-not IPAH, IPAH, retransplant) had worse 1-year mortality than COPD without A1ATD (Figure 8; eSlide LU 90). Regarding 5-year mortality (Figure 10; eSlide LU 114), those transplanted for CF or LAM/tuberous sclerosis had a lower risk of death than those transplanted for COPD without A1ATD. For conditional 5-year mortality (Figure 11; eSlide LU 122), similar diagnostic trends were seen, with the addition of COPD with A1ATD having a lower risk. In the 10-year mortality model, only those transplanted for LAM/tuberous sclerosis had a lower risk of death than those transplanted for COPD without A1ATD (eSlide LU127).
Among adult lung transplants performed for COPD without A1ATD (N = 10,992) between January 2002 and June 2014, the pre- and peri-transplant categorical risk factors significantly associated with mortality during first post-transplant year in multivariable analyses included earlier transplant era, recipient male gender, recipient steroid use, donor diabetes and increased severity of recipient illness at the time of transplantation (i.e., hospitalization). Continuous risk factors significantly associated with mortality included lower transplant center volume, greater negative donor height minus recipient height difference (i.e., donor shorter than recipient) and older recipient age at transplant (eSlides LU 102 to 106). The increased risk of 1-year post-transplant mortality with older recipient age began just below 60 years and rose thereafter (eSlide LU 104).
Among adult lung transplants performed for IIP (N = 9,491) between January 2002 and June 2014, the pre- and peri-transplant categorical risk factors significantly associated with mortality during the first post-transplant year in multivariable analyses included earlier transplant era, higher mismatching of donor and recipient human leukocyte antigen (HLA) type, non-identical donor and recipient blood groups, CMV mismatch and increased severity of recipient illness at the time of transplantation (i.e., hospitalization). Continuous risk factors significantly associated with mortality included lower transplant center volume, elevated total bilirubin, higher level of supplemental oxygen required at rest and older recipient and donor age at transplant (eSlides LU 107 to 113). The increased risk of 1-year post-transplant mortality with older recipient age began at just above 60 years and rose thereafter (eSlide LU 109).
Acute and chronic lung rejection
Based on follow-ups between July 2004 and June 2015, 4,064 of 14,516 (28%) adult lung transplant–surviving recipients with known rejection status had at least 1 episode of treated rejection between discharge and 1-year follow-up (eSlide LU 40).
BOS, conditional on surviving to 2 weeks after transplant (to avoid biases introduced by early mortality), remained a common long-term complication. For transplants performed between January 1994 and June 2014, Kaplan-Meier time-to-event analysis of primary adult lung transplant recipients (N = 20,171) estimated that just under 50% of patients developed BOS within 5 years of transplantation, and 76% developed BOS by 10 years post-transplant. When limited to only those adult lung recipients who survived and had data reported for every annual follow-up through 5 years post-transplant, the BOS rate was 41.5% at 5 years (eSlide LU 69). The Kaplan-Meier BOS rate was higher among retransplants (N = 715)—63% at 5 years, and 81% at 10 years after retransplant (eSlide LU 73).
Lung transplant recipients who had a primary indication of COPD without A1ATD, COPD with A1ATD, IIP or ILD-not IIP had a similar risk of BOS (Figure 12; eSlide LU 74). However, patients with CF had somewhat higher BOS-free survival in the long-term compared to COPD without A1ATD. Recipients undergoing retransplant had a higher rate of BOS frequency compared with those undergoing primary lung transplant for COPD without A1ATD.
Figure 12Adult lung transplant recipient bronchiolitis obliterans syndrome–free survival (BOS), by primary diagnostic indication for transplant, conditional on survival to 14 days (transplants: January 1994 to June 2014).
Morbidities commonly caused or exacerbated by immunosuppressive medicines (e.g., hypertension, renal dysfunction, diabetes and hyperlipidemia) occurred frequently after lung transplantation (Table 6), and the complication rates continued to increase as length of follow-up increased (eSlides LU 69 and 71). Based on Kaplan-Meier estimates, lung transplant recipients had a high incidence of severe renal dysfunction. Within 5 years after transplantation, 24% of recipients had creatinine >2.5 mg/dl, dialysis or renal transplant, and 41% had at least 1 of these common morbidities within 10 years (eSlide LU 79).
Percentage of patients with known responses who experienced various morbidities as reported on forms at or before the 1-year annual follow-up after transplantation.
in Adult Lung Transplant Survivors Within 1 Year Post-transplant (Transplants: January 1994 to June 2014)
N refers to the count of patients with a known response.
Hypertension
52.7%
6,237
48.4%
949
45.9%
2,542
53.7%
5,092
52.2%
732
Renal dysfunction
24.9%
7,101
24.9%
1,035
18.0%
2,927
21.6%
6,129
22.2%
972
Creatinine ≤2.5 mg/dl
17.2%
17.4%
12.3%
15.1%
15.3%
Creatinine >2.5 mg/dl
6.0%
6.1%
4.1%
4.4%
4.3%
Chronic dialysis
1.7%
1.4%
1.5%
1.9%
2.5%
Renal transplant
0.1%
0.0%
0.0%
0.1%
0.1%
Hyperlipidemia
29.0%
6,446
23.0%
990
9.3%
2,640
34.2%
5,265
26.6%
773
Diabetes
19.7%
7,187
14.7%
1,047
37.1%
2,981
22.2%
6,335
17.2%
1,049
BOS
9.3%
6,759
10.9%
1,003
8.8%
2,821
8.6%
5,986
7.4%
952
Only includes patients with responses reported on every follow-up through the 1-year annual follow-up. Refer to Table 1 for abbreviations.
a Percentage of patients with known responses who experienced various morbidities as reported on forms at or before the 1-year annual follow-up after transplantation.
b N refers to the count of patients with a known response.
Overall malignancy rates increased as the length of follow-up increased after lung transplantation; 23% of recipients at 5 years post-transplantation and 42% at 10 years post-transplantation had cancer based on Kaplan-Meier estimates (eSlide LU 82). Skin cancer was the most frequently reported of all cancers. However, post-transplant lymphoproliferative disease (PTLD) and other malignancies remained as prominent morbid conditions.
Among the more common diagnostic indications for adult lung transplant, those transplanted for CF had greater frequency of diabetes and a lower frequency of hyperlipidemia post-transplant within 1 year (Table 6; eSlides LU 160 to 165) and within 5 years. The diagnostic groups had a similar frequency of systemic hypertension (approximately 80%) and renal dysfunction (approximately 50%) within the first 5 post-transplant years. Of note, the retransplant group had a higher frequency of BOS within the first year and within the first 5 years after transplantation (eSlides LU 160 to 165).
Heart–lung transplantation
Centers and transplant activity
The Registry now contains data from 3,879 adult heart–lung transplants that occurred through June 30, 2015. The relatively low volume of adult heart–lung transplants performed in the past decade (i.e., 49 to 92 transplants per year) and reported to the Registry probably reflects a combination of advances in non-transplant treatments and lower threshold to perform isolated heart or lung transplant where a combined heart–lung transplant may have been considered in the past (Figure 13; eSlide HL 4).
Figure 13Number of adult heart–lung transplants by year (transplants: 1982 to 2014). This figure includes only the adult heart–lung transplants that were reported to the ISHLT Registry and does not represent the number of adult heart–lung transplants performed worldwide.
In 2014, 40 participating centers reported the 58 adult heart–lung transplants. Based on transplants performed between January 2009 and June 2015, 27% of procedures occurred at the 4 centers (5% of centers) that averaged 4 to 9 procedures per year, 14% occurred at the 4 centers (5% of centers) that averaged 3 procedures per year, and 58% of the heart–lung transplant procedures occurred at 72 centers (90% of centers) that averaged only 1 or 2 heart–lung transplants per year (eSlide HL 5).
Indications and other recipient characteristics
For the 3,397 heart–lung transplants that occurred from January 1982 through June 2015 and for whom diagnosis was reported, approximately two thirds had an indication of congenital heart disease or IPAH (eSlide HL 7). Figure 14 (eSlide HL 9) shows the distribution of primary indication for heart–lung transplant over time. The proportion of adult transplants for diagnoses of congenital heart disease and IPAH remained relatively unchanged. The proportion of transplant for CF decreased somewhat and the proportion of patients transplanted for cardiomyopathy increased somewhat. Sizable geographic differences in the major indications for heart and lung transplant were observed during the past decade. The higher proportion of patients transplanted for congenital heart disease in other regions outside of Europe and North America may have occurred because of differences in access to corrective surgery during childhood. A relatively high proportion of patients undergo transplant for PAH in Europe, as compared with North America and other geographic regions. These differences may reflect different allocation policies among the regions (Figure 15; eSlide HL 12).
Figure 14Adult heart–lung transplantation according to major indication and year of transplantation (transplants: 1990 to 2014). CHD, congenital heart disease; PAH, pulmonary arterial hypertension; CF, cystic fibrosis; CM, cardiomyopathy; COPD without A1ATD, chronic obstructive pulmonary disease (COPD) not associated with α1-antitrypsin deficiency (A1ATD); ILD, interstitial lung disease.
Figure 15Adult heart–lung transplant primary diagnostic indication for transplantation distribution by location (transplants: January 2004 to June 2015; total: N = 812; Europe: N = 424; North America: N = 330; other: N = 58). Transplants with unknown diagnoses excluded (total: N = 71; Europe: N = 60; North America: N = 1; other: N = 10). COPD with A1ATD, α1-antitrypsin deficiency–associated chronic obstructive pulmonary disease; ILD, interstitial lung disease; COPD without A1ATD, chronic obstructive pulmonary disease (COPD) not associated with A1ATD; CM, cardiomyopathy; CF, cystic fibrosis; PAH, pulmonary arterial hypertension; CHD, congenital heart disease.
Retransplantation as a diagnostic indication was rare, with only 57 heart–lung recipients having had a heart–lung retransplant between January 1982 through June 2015 (eSlide HL 7).
Because the indications for heart–lung transplants have changed over time, we focused on the recent era where transplants occurred January 2004 through June 2015 (Table 7). During this period, the 3 most frequent indications were cardiovascular disease categories of congenital heart disease (35%), pulmonary arterial hypertension (27%) and cardiomyopathy (11%). Only 9 (1% of all heart–lung transplants) patients underwent retransplant.
Diagnostic groupings based on reporting classification categories; recipients may have had secondary diagnoses that overlapped with other categories (e.g., sarcoidosis with ILD and PAH). Diagnostic misclassification may have occurred.
for Adult Heart‒Lung Transplants (Transplants January 2004 to June 2015; N = 812)
a Diagnostic groupings based on reporting classification categories; recipients may have had secondary diagnoses that overlapped with other categories (e.g., sarcoidosis with ILD and PAH). Diagnostic misclassification may have occurred.
b Likely includes other types of World Health Organization (WHO) Group 1 pulmonary arterial hypertension.
Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung and heart–lung transplant report—2013; Focus theme: age.
An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
For 3,775 primary heart–lung transplants performed between January 1982 and June 2014, recipients had survival rates of 71% at 3 months, 63% at 1 year, 52% at 3 years, 45% at 5 years and 32% at 10 years (eSlide HL 16). Survival after heart–lung transplant has improved with transplant era, such that median survival for patients transplanted between 2004 and June 2014 has improved to 5.8 years (Figure 16; eSlide HL 17). Recipients in the most recent era had a median survival, conditional on survival to 1 year after transplant, of >10 years. In comparison to lung-only transplantation (Figure 5; eSlide LU 20), primary heart–lung transplantation had a more pronounced early mortality but a better long-term survival.
Figure 16Adult heart–lung transplant recipient Kaplan-Meier survival by era (transplants: 1982 to 1993, 1994 to 2003 and 2004 to June 2014). Conditional median survival is the time to 50% survival for the subset of recipients alive 1 year after transplantation.
Regarding survival after heart–lung transplant stratified by diagnosis, patients transplanted for CF had better survival compared with those transplanted for COPD without A1ATD (Figure 17; eSlide HL 18). Although other diagnostic categories showed numerical differences in survival, the small numbers of patients may have limited the ability to demonstrate statistically significant differences.
Figure 17Adult heart–lung transplant recipient Kaplan-Meier survival by primary diagnostic indication for transplantation (transplants: January 1990 to June 2014). CM, cardiomyopathy; COPD without A1ATD, chronic obstructive pulmonary disease (COPD) not associated with A1ATD; CF, cystic fibrosis; ILD, interstitial lung disease; CHD, congenital heart disease; PAH, pulmonary arterial hypertension.
For heart–lung transplant recipients who had the 2 most common diagnostic indications (i.e., CHD and PAH), based on reported deaths between January 1992 and June 2015, the most common identifiable causes of death in the first 30 days post-transplant were graft failure (lung or heart) and technical complications. Of deaths within 30 days, those transplanted for PAH had a higher percentage of deaths due to non-CMV infections (Table 8; eSlides HL 54and 55). After the first year, OB/BOS/late graft failure (lung or heart) and non-CMV infections were the most common causes of mortality. Cardiovascular causes of death accounted for a smaller, but important, proportion of the deaths.
Table 8Known Causes of Death Within 0 to 30 Days and >5 Years Post-transplant for Adult Heart‒Lung Transplant Recipients,
Some misclassification may have occurred among the cause of death terms of graft failure, bronchiolitis and acute rejection. Graft failure, due to variation in reporting, may represent acute rejection, primary graft dysfunction or other causes early post-transplant, or bronchiolitis obliterans syndrome or other causes late post-transplant.
0 to 30 days
>5 years
CHD (N = 164)
PAH (N = 93)
CHD (N = 160)
PAH (N = 117)
OB/BOS
0
0
43 (26.9%)
29 (24.8%)
Graft failure
46 (28.0%)
28 (30.1%)
31 (19.4%)
17 (14.5%)
Acute rejection
2 (1.2%)
1 (1.1%)
1 (0.6%)
1 (0.9%)
Infection, non-CMV
14 (8.5%)
24 (25.8%)
29 (18.1%)
21 (17.9%)
CMV
0
0
0
1 (0.9%)
Malignancy, other
0
1 (1.1%)
5 (3.1%)
14 (12.0%)
Lymphoma
0
0
6 (3.8%)
0
Cardiovascular
16 (9.8%)
4 (4.3%)
16 (10.0%)
15 (12.8%)
Technical
46 (28.0%)
18 (19.4%)
1 (0.6%)
1 (0.9%)
Multiple-organ failure
17 (10.4%)
7 (7.5%)
10 (6.3%)
5 (4.3%)
Other
23 (14.0%)
10 (10.8%)
18 (11.3%)
13 (11.1%)
Data expressed as number (percentage of deaths out of all deaths with known cause in the respective time period). Refer to Table 1 for other abbreviations.
a Includes primary transplants and retransplants.
b Some misclassification may have occurred among the cause of death terms of graft failure, bronchiolitis and acute rejection. Graft failure, due to variation in reporting, may represent acute rejection, primary graft dysfunction or other causes early post-transplant, or bronchiolitis obliterans syndrome or other causes late post-transplant.
The 2 cohorts with CHD or PAH as the diagnostic indication for transplant showed significant differences in cause of death at the early and later time-points (Table 8), but these were not adjusted for other factors. For example, the PAH group had a higher proportion of patients who had non-CMV infection as an early cause of death, whereas the CHD group had a higher proportion of patients who died from a cardiovascular or a technical issue. For later causes of death, the PAH group had a higher proportion of patients who died from malignancy in comparison to the CHD group.
Lung allograft dysfunction (e.g., OB/BOS) played a significant role in the cause of late death, a unique feature of heart–lung transplant recipients in comparison to heart transplant recipients.
The Registry of the International Society for Heart and Lung Transplantation: thirty-third official adult heart transplantation report—2016; Focus theme: Primary diagnostic indications for transplant.
Heart–lung recipients who subsequently had a heart–lung retransplant had similar causes of death compared with primary lung transplant, lung retransplant and primary heart–lung transplant recipients, although this relatively small number of transplant recipients had a relatively low number of events (eSlides LU 86 and HL 37).
Heart–lung rejection
In heart–lung transplant recipients, coronary artery vasculopathy (CAV) occurred less frequently than BOS at all time-points, based on follow-up data for transplants from January 1994 to June 2014 (Figure 18; eSlide HL 32). At 1, 3, 5 and 10 years after heart–lung transplantation, 8%, 27%, 42% and 62% of recipients developed BOS in comparison to 3%, 7%, 9% and 27% who developed CAV, respectively.
Figure 18Adult heart–lung transplant coronary artery vasculopathy (CAV) and bronchiolitis obliterans syndrome–free survival (BOS) (adult heart–lung transplants: April 1994 to June 2014).
Morbidities often associated with immunosuppressive therapy commonly occurred at both the 1-year and 5-year time-points after heart–lung transplantation, with these rates increasing over time (Table 9). Of all malignancies, lymphoma occurred most commonly, especially in the first post-transplant year (eSlides HL 34 and 35).
Table 9Cumulative Morbidity Rates in Adult Heart‒Lung Transplant
Percentage of patients with known responses who experienced various morbidities as reported on forms at or before the 1-year and 5-year annual follow-up forms after transplantation. Only includes patients with responses reported on every follow-up through the 5-year annual follow-up.
Percentage of patients with known responses who experienced various morbidities as reported on forms at or before the 1-year and 5-year annual follow-up forms after transplantation. Only includes patients with responses reported on every follow-up through the 5-year annual follow-up.
Total number with known response
Hypertension
59.1%
433
87.2%
180
Renal dysfunction
19.6%
496
42.6%
235
Abnormal creatinine ≤ 2.5 mg/dl
11.9%
28.1%
Creatinine >2.5 mg/dl
3.2%
10.6%
Chronic dialysis
4.2%
3.0%
Renal transplant
0.2%
0.9%
Hyperlipidemia
28.0%
453
70.4%
189
Diabetes
17.7%
508
28.7%
247
Coronary artery vasculopathy
3.0%
396
7.5%
120
Bronchiolitis obliterans syndrome
7.5%
466
30.7%
205
a Combined group of primary transplants and retransplants.
b Percentage of patients with known responses who experienced various morbidities as reported on forms at or before the 1-year and 5-year annual follow-up forms after transplantation. Only includes patients with responses reported on every follow-up through the 5-year annual follow-up.
Thanks to the data reporting efforts of participating transplant centers and collectives worldwide, this report provides comprehensive and current information regarding developments and challenges in adult lung and heart–lung transplantation. Over the decades, the number of lung transplants reported has increased while the number of heart–lung transplants reported has declined. When comparing different eras, survival for both transplant types has improved over time, mainly due to improved survival in the early post-transplant period. Morbidities after lung and heart–lung transplantation occurred frequently, and the main long-term contributors to decreased long-term survival in both groups consisted of BOS and infections. Lung and heart–lung transplant recipients who underwent retransplantation showed consistently worse morbidity and mortality than primary recipients of the same organs.
This year’s Registry Report theme of diagnostic indication for transplant has explored in detail the influence of the diagnostic indication for transplant on post-transplant survival and morbidity. We also described important regional variations that reflect differences in lung disease demographics, treatment approaches, patient selection and organ allocation around the world. The new information provided in this report regarding patients’ characteristics, outcomes and predictors of outcomes among the diagnostic indications for adult lung transplantation will hopefully stimulate further research aimed at improving candidate selection and post-transplant outcomes.
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.
The Registry of the International Society for Heart and Lung Transplantation: thirty-third official adult heart transplantation report—2016; Focus theme: Primary diagnostic indications for transplant.
The Registry of the International Society for Heart and Lung Transplantation: nineteenth official pediatric heart transplantation report—2016; Focus theme: Primary diagnostic indications for transplant.
The Registry of the International society for Heart and Lung Transplantation: nineteenth official pediatric lung and heart–lung transplantation report—2016; Focus theme: Primary diagnostic indications for transplant.
The Registry of the International Society for Heart and Lung Transplantation: thirty-first adult lung and heart–lung transplant report—2014; Focus theme: retransplantation.
An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung and heart–lung transplant report—2013; Focus theme: age.
The Registry of the International Society for Heart and Lung Transplantation: thirty-second adult lung and heart–lung transplant report—2015; Focus theme: early graft failure.
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