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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Lung And Heart-Lung Transplantation Report—2017; Focus Theme: Allograft ischemic time

      This 34th Adult Lung and Heart-Lung Transplant Report summarizes data from 60,107 adult lung and 3,992 adult heart-lung transplants performed through June 30, 2016, and reported to the International Society for Heart and Lung Transplantation (ISHLT) 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 allograft ischemic time. We report geographic, center, donor, and recipient factors associated with variations in allograft ischemic time, associations of allograft ischemic time 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/).

      Statistical methods

      Data collection, conventions, and statistical methods

      National and multinational organ/data exchange organizations and individual centers submitted data to the ISHLT Registry. Since the Registry’s inception, 472 heart transplant centers, 256 lung transplant centers, and 180 heart-lung transplant centers have reported data to the Registry.
      • Lund L.H.
      • Khush K.
      • Cherik W.S.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: thirty-fourth adult heart transplantation report—2017; focus theme: allograft ischemic time.
      • Rossano J.W.
      • Cherik W.S.
      • Goldfarb S.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: twentieth pediatric heart transplantation report—2017; focus theme: allograft ischemic time.
      • Goldfarb S.B.
      • Levvey B.J.
      • Edwards L.B.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: twentieth pediatric lung and heart-lung transplantation report—2017; focus theme: allograft ischemic time.
      We estimate that data submission to the Registry represents approximately 75% of the worldwide thoracic transplant activity.
      This report presents an overview of donor and recipient characteristics and outcomes. Additional and extended analyses presented in 5 separate online slide sets (“Introduction,” “ Lung Overall,” “Adult Lung Transplant,” “Heart-Lung Overall,” and “Adult Heart-Lung Transplant” http://ishlt.org/registries/slides.asp?slides=heartLungRegistry) supplement the report. The ISHLT Web site also contains slide sets for previous annual reports. This report references specific online e-slides when particular data are discussed but not shown because of space limitations. The e-slide numbers refer to the online adult lung, shortened to L(a), and adult heart-lung, noted as HL(a) transplant slides.
      The Registry Web site (http://ishlt.org/registries/heartLungRegistry.asp) provides detailed spreadsheets of the data elements collected in the Registry. The Registry requires submission of core donor, recipient, and transplant procedure variables at baseline (i.e., around the time of transplantation) and at yearly follow-up, and these variables therefore have low rates of missingness. Nevertheless, data quality depends on the accuracy and completeness of reporting. Rates of missingness may significantly increase for Registry variables that depend on voluntary reporting. The Registry uses various quality control measures to ensure acceptable data quality and completeness before including data for analyses.

      Analytical conventions

      Unless otherwise specified, analyses of lung transplants do not include heart-lung transplant data. Retransplant includes those with a previously reported transplant of the same organ type or the same organ type along with another solid organ or those with a retransplant diagnosis.
      • Yusen R.D.
      • Edwards L.B.
      • Kucheryavaya A.Y.
      • 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.
      This approach to determining retransplants may slightly underestimate the number of retransplant events. The Registry does not capture the exact occurrence date for most secondary outcomes (e.g., renal dysfunction) but does capture the window of occurrence (i.e., the event occurred between the first and the second year annual follow-up visits). For the report’s analyses, we use the midpoint between the annual follow-ups as a surrogate for the event date. On the follow-up where a death is reported, some underreporting of secondary outcomes and other information likely occurs. Thus, to reduce the possibility of underestimating event rates or other outcomes, we restrict some analyses to include only surviving recipients.
      For time-to-event and cumulative morbidity analyses, we censor the follow-up of recipients who do 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 truncate time-to-event graphs (e.g., survival graphs) when the number of individuals at risk becomes <10. The Supplementary Material available online (www.ishltonline.org) includes additional information regarding the general statistical methods used for analyses and data interpretation. Previous Registry report themes provide more details regarding specific donor
      • Yusen R.D.
      • Christie J.D.
      • Edwards L.B.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung and heart-lung transplant report—2013; focus theme: age.
      and recipient characteristics
      • Yusen R.D.
      • Christie J.D.
      • Edwards L.B.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung and heart-lung transplant report—2013; focus theme: age.
      • Yusen R.D.
      • Edwards L.B.
      • Dipchand A.I.
      • et al.
      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.
      and recipient outcomes.
      • Yusen R.D.
      • Edwards L.B.
      • Kucheryavaya A.Y.
      • 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.
      • Yusen R.D.
      • Edwards L.B.
      • Kucheryavaya A.Y.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: thirty-second official adult lung and heart-lung transplantation report—2015; focus theme: early graft failure.

      Focus Theme Methods: Allograft ischemic time

      The Registry Steering Committee selected allograft ischemic time as the theme topic for the 2017 report given the rapid expansion of donation after circulatory death transplantation, which may entail substantial warm allograft ischemic time, and the emergence of ex vivo organ perfusion (and ventilation, for lung transplant) systems that significantly affect allograft ischemic times.
      Lung allograft ischemic time was defined as the time that elapsed between aortic cross-clamp performed during organ procurement surgery and lung allograft reperfusion during lung transplant surgery. For bilateral lung transplants, reperfusion of the second lung defined the end of the allograft ischemic time. Heart-lung allograft ischemic time was defined as the time that elapsed between aortic cross-clamp performed during organ procurement surgery and reperfusion of the last transplanted organ.
      The reporting of allograft ischemic time varied significantly by geographic region, with high rates of data completeness from North American transplant centers, low rates of completeness from European centers, and moderate rates for centers from regions outside Europe and North America. Thus, we recommend cautious interpretation of the theme data, especially for analyses that include geographic region and for generalizability to non-North American centers. The inconsistent reporting of different variables from different regions illustrates the trade-offs between worldwide broadly generalizable Registry data vs more internally valid but less generalizable data collected locally or regionally.

      Lung transplantation

      Centers and transplant activity

      The Registry now contains data from 60,107 adult lung transplants performed through June 2016. Data were submitted from 140 participating transplant centers for a total of 4,122 adult lung transplantation procedures performed in 2015. Figure 1 (eSlide L(a) 4) shows the number of reported adult lung transplants each year stratified by procedure type. The upward trend for reported overall and bilateral lung transplant activity during the past 3 decades has slowed in the last 3 years. The proportion of reported single lung transplants became smaller than that for bilateral lung transplants about 15 years ago, and the number of single lung transplants has recently remained fairly stable.
      Figure 1
      Figure 1Number of adult lung transplants reported to the International Society for Heart and Lung Transplantation Registry by year and procedure type (transplants: 1985–2015).
      A total of 170 centers reported at least 1 adult lung transplant performed between January 2009 and June 2016 (Figure 2, eSlide L(a) 7). Most transplant activity has again occurred in a relatively few high-volume centers. Of the 170 centers, 48 (28%) had an average activity of 30 or more transplants per year and performed almost 66% of the transplant procedures, 18 (11%) had an average activity of 50 or more transplants per year and performed 37% of procedures, and 56 centers (33%) averaged fewer than 10 transplants per year and performed just 4% of the procedures. Pediatric lung transplantation remains a much less commonly reported procedure, with only 138 (2% of total reported lung transplants) performed between 2015 and June 2016 (eSlide L(p) 6).
      • Goldfarb S.B.
      • Levvey B.J.
      • Edwards L.B.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: twentieth pediatric lung and heart-lung transplantation report—2017; focus theme: allograft ischemic time.
      Figure 2
      Figure 2Average adult lung transplant center volume by location (transplants: 2009–June 2016).

      Indications and other recipient characteristics

      Table 1 reports the primary diagnostic indications for adult lung transplantation,
      • Yusen R.D.
      • Edwards L.B.
      • Dipchand A.I.
      • et al.
      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.
      stratified by procedure type and associated counts and proportions of patients who received a transplant for each indication during the past 2 decades. Chronic obstructive pulmonary disease (COPD) without α-1-anti-trypsin deficiency remains the most common indication for transplantation (31%). The combined group of COPD, with (5%) or without α-1-anti-trypsin deficiency, totalled more than 33% of all lung transplants. The second most common indication consisted of the broad category of interstitial lung disease or pulmonary fibrosis (30%), mainly consisting of idiopathic interstitial pneumonia (IIP; 24.8%) and non-IIP interstitial lung disease (5.5%).
      • Travis W.D.
      • Costabel U.
      • Hansell D.M.
      • et al.
      An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
      The third most common indication consisted of bronchiectasis, mainly consisting of cystic fibrosis (16%), presumably associated with bronchiectasis, whereas non–cystic fibrosis bronchiectasis (2.7%) made up a much lower proportion of transplants. Idiopathic pulmonary arterial hypertension (2.9%) also represented a low proportion, as did non–idiopathic pulmonary arterial hypertension pulmonary hypertension (1.5%). Last year’s report contained a detailed analysis of indications for transplant and their effect on outcomes.
      • Yusen R.D.
      • Edwards L.B.
      • Dipchand A.I.
      • et al.
      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.
      Table 1Primary Indications for Adult Lung Transplant Stratified by Procedure Type (Transplants: January 1995–June 2016)
      SLTBLTTotal
      (n = 18,207)(n = 36,046)(N = 54,253)
      Diagnosis
      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 misclassification may occur.
      No. (%)No. (%)No. (%)
      COPD8,063 (44.3)11,451 (31.8)19,514 (36.0)
       Without A1ATD7,266 (39.9)9,539 (26.5)16,805 (31.0)
       With A1ATD797 (4.4)1,912 (5.3)2,709 (5.0)
      ILD7,527 (41.3)8,915 (24.7)16,442 (30.3)
       IIP
      Categories may include other types of IIP and non-IIP.8
      6,449 (35.4)6,990 (19.4)13,439 (24.8)
       ILD-not IIP
      Categories may include other types of IIP and non-IIP.8
      1,078 (5.9)1,925 (5.3)3,003 (5.5)
      Bronchiectasis285 (1.6)9,679 (26.9)9,964 (18.4)
       CF
      Presumably associated with bronchiectasis.
      218 (1.2)8,266 (22.9)8,484 (15.6)
       Non–CF-bronchiectasis67 (0.4)1,413 (3.9)1,480 (2.7)
      PAH223 (1.2)2,171 (6.0)2,394 (4.4)
       IPAH
      Likely includes other types of World Health Organization Group 1 PAH.9
      88 (0.5)1,481 (4.1)1,569 (2.9)
       PH-not IPAH135 (0.7)690 (1.9)825 (1.5)
      Less common diagnoses1,187 (6.5)2,561 (7.1)3,748 (6.9)
       Sarcoidosis312 (1.7)1,026 (2.8)1,338 (2.5)
       LAM/tuberous sclerosis146 (0.8)381 (1.1)527 (1.0)
       OB73 (0.4)395 (1.1)468 (0.9)
       CTD140 (0.8)282 (0.8)422 (0.8)
       Cancer7 (0.0)27 (0.1)34 (0.1)
       Other509 (2.8)450 (1.2)959 (1.8)
      Retransplant
      Retransplant includes those with a previously reported lung or heart-lung transplant or a retransplant diagnosis.4
      922 (5.1)1,269 (3.5)2,191 (4.0)
      A1ATD, α-1-anti-trypsin deficiency; BLT, bilateral lung transplant; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; CTD; connective tissue disease; IIP, idiopathic interstitial pneumonia; ILD, interstitial lung disease; IPAH, idiopathic pulmonary arterial hypertension; LAM, lymphangioleiomyomatosis; OB, obliterative bronchiolitis; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; SLT, single lung transplant.
      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 misclassification may occur.
      b Categories may include other types of IIP and non-IIP.
      • Travis W.D.
      • Costabel U.
      • Hansell D.M.
      • et al.
      An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
      c Presumably associated with bronchiectasis.
      d Likely includes other types of World Health Organization Group 1 PAH.
      • Simonneau G.
      • Robbins I.M.
      • Beghetti M.
      • et al.
      Updated clinical classification of pulmonary hypertension.
      e Retransplant includes those with a previously reported lung or heart-lung transplant or a retransplant diagnosis.
      • Yusen R.D.
      • Edwards L.B.
      • Kucheryavaya A.Y.
      • 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.

      Induction immunosuppression therapy

      Among adults who underwent lung transplantation between January 2004 and June 2016, received post-transplant prednisone, and survived to hospital discharge (n = 19,656 with known induction status), 60% received induction therapy (eSlide L(a) 48). Of the recipients who received any induction therapy, the proportion receiving an interleukin-2 antagonist has increased over time, with more than 80% receiving an interleukin-2 antagonist in recent years (Figure 3, eSlide L(a) 50). The proportion of patients receiving polyclonal anti-lymphocyte globulin/anti-thymocyte globulin has continued to fall, while a small but relatively static proportion of patients have received alemtuzumab.
      Figure 3
      Figure 3Induction immunosuppression for adult lung transplant recipients by year (transplants: 2004–2015). ALG/ATG, anti-lymphocyte globulin/anti-thymocyte globulin; IL-2R, interleukin 2 receptor.

      Maintenance immunosuppression therapy

      For adult lung transplant recipients who received post-transplant prednisone and survived to hospital discharge, maintenance immunosuppression consisting of tacrolimus plus mycophenolate mofetil/mycophenolic acid remained the most common regimen at 1 year after transplant (Figure 4, eSlide L(a) 54). The use of cyclosporine and azathioprine has gradually decreased during the past decade.
      Figure 4
      Figure 4Maintenance immunosuppression for adult lung transplant recipients at the 1-year follow-up (follow-ups: 2004–June 2016). MMF/MPA, mycophenolate mofetil/mycophenolic acid.

      Survival

      Adults who underwent primary lung transplantation between January 1990 and June 2015 (N = 53,396) had a median survival of 6.0 years. The recipients who survived to 1 year after primary transplant had a conditional median survival of 8.1 years. In unadjusted analyses, bilateral lung transplant recipients had better survival than unilateral recipients beginning in the first year after transplant, and this difference increased during the next 14 years of follow-up (Figure 5, eSlide L(a) 19): both groups had 93% to 94% survival at 1 month, with survival of 90% and 88% for bilateral and unilateral, respectively, at 3 months, 82% and 78% at 1 year, 69% and 61% at 3 years, 59% and 48% at 5 years, and 41% and 23% at 10 years (p < 0.0001, Kaplan-Meier). Retransplantation continues to have inferior survival compared with primary transplantation, with first retransplant survival of 86% at 1 month, 67% at 1 year, 40% at 5 years, and 21% at 10 years (eSlide L(a) 20). Aside from retransplantation, post-transplant unadjusted survival remains highly associated with the indication for transplantation, with patients who receive transplants for cystic fibrosis experiencing superior long-term survival compared with all other diagnoses (eSlide L(a) 26).
      Figure 5
      Figure 5Kaplan-Meier survival for adult lung transplant recipients by procedure type (transplants: 1990–June 2015). Conditional median survival is the estimated time to 50% survival for the sub-set of recipients alive at 1 year after transplantation (p < 0.0001 by log-rank test statistic).
      Causes of death after adult lung transplantation differ between the early and the late postoperative periods (Table 2). An analysis of deaths reported from 1990 through June 2016 shows that infection and the combination of the various types of reported graft failure, including obliterative bronchiolitis (OB)/bronchiolitis obliterans syndrome (BOS), acute rejection, and “graft failure,”
      • Yusen R.D.
      • Edwards L.B.
      • Kucheryavaya A.Y.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: thirty-second official adult lung and heart-lung transplantation report—2015; focus theme: early graft failure.
      remained the leading causes of death between 30 days and 1 year after transplant, accounting for 36.8% and 22.7% of deaths, respectively. Beyond the first year, the combination of types of reported graft failure became the leading cause of death, accounting for more than 40% of the deaths. Post-transplant lymphoproliferative disorder (lymphoma) caused a small but significant number of deaths, while non-lymphoma malignancy became an increasingly common cause of death after the first post-transplant year.
      Table 2Known Causes of Death for Adult Lung Transplant Recipients (Deaths: January 1990–June 2016)
      0–30 days31 days–1 year>1–3 years>3–5 years>5–10 years>10 years
      Cause of death
      Data are expressed as number (%). Data in parentheses indicate percentage of deaths out of all deaths with known cause in the respective time period.
      ,
      Some misclassification may occur among the cause of death terms of bronchiolitis, and acute rejection, and graft failure; Owing to variation in reporting, graft failure may represent acute rejection, primary graft dysfunction, or other causes of death early post-transplant, or non-OB/BOS cause of chronic lung allograft dysfunction or other causes of death late after transplant.
      (n = 3,574)(n = 6,367)(n = 6,194)(n = 3,656)(n = 4,578)(n = 1,837)
      OB/BOS10 (0.3)292 (4.6)1,633 (26.4)1,095 (30.0)1,146 (25.0)407 (22.2)
      Graft failure870 (24.3)1,039 (16.3)1,162 (18.8)651 (17.8)737 (16.1)277 (15.1)
      Acute rejection115 (3.2)114 (1.8)92 (1.5)20 (0.5)21 (0.5)4 (0.2)
      Infection (CMV and non-CMV)685 (19.2)2,342 (36.8)1,345 (21.7)664 (18.1)791 (17.3)304 (16.5)
      Malignancy
       Non-lymphoma5 (0.1)193 (3.0)514 (8.3)430 (11.8)676 (14.8)258 (14.0)
       Lymphoma1 (0.0)137 (2.2)107 (1.7)54 (1.5)83 (1.8)56 (3.0)
      Cardiovascular429 (12.0)345 (5.4)275 (4.4)173 (4.7)267 (5.8)120 (6.5)
      Technical414 (11.6)226 (3.5)55 (0.9)17 (0.5)33 (0.7)13 (0.7)
      Multiple organ failure440 (12.3)766 (12.0)319 (5.2)151 (4.1)213 (4.7)98 (5.3)
      Other605 (16.9)913 (14.3)692 (11.2)401 (11.0)611 (13.3)300 (16.3)
      BOS, bronchiolitis obliterans syndrome; CMV, cytomegalovirus; OB, obliterative bronchiolitis.
      a Data are expressed as number (%). Data in parentheses indicate percentage of deaths out of all deaths with known cause in the respective time period.
      b Some misclassification may occur among the cause of death terms of bronchiolitis, and acute rejection, and graft failure; Owing to variation in reporting, graft failure may represent acute rejection, primary graft dysfunction, or other causes of death early post-transplant, or non-OB/BOS cause of chronic lung allograft dysfunction or other causes of death late after transplant.
      Unadjusted survival after adult lung transplantation has changed during the last 3 decades, with the 2 recent eras showing better survival compared with the first era, mainly due to improvements in short-term survival (Figure 6, eSlide L(a) 21). However, the intermediate-term survival of the most recent era has dropped toward the survival rate of the previous era, despite superior 30-day and 1-year survival. Although 1-year survival has steadily increased across the three eras (72% for 1990–1998, 80% for 1999–2008, and 84% for 2009–June 2015), 5-year survival (46%, 55%, and 57%, respectively) has not changed significantly between the more recent eras 2 and 3, so that median survival for the 2 most recent eras will likely be similar. Of note, medium-term survival for pediatric lung transplant recipients has shown a similar trend.
      • Goldfarb S.B.
      • Levvey B.J.
      • Edwards L.B.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: twentieth pediatric lung and heart-lung transplantation report—2017; focus theme: allograft ischemic time.
      Figure 6
      Figure 6Kaplan-Meier survival for adult lung transplant recipients by transplant era (transplants: 1990–June 2015: 1990–1998 vs 1999–2008: p < 0.0001; 1990–1998 vs 2009–June 2015: p < 0.0001; 1999–2008 vs 2009–June 2015: p < 0.0001, log-rank test statistic with adjustments for multiple comparisons using Scheffe’s method).
      Serologic evidence of previous exposure to cytomegalovirus (CMV) in the recipient or donor, or both, continued to show a significant difference in post-transplant unadjusted survival (Figure 7, eSlide L(a) 42). Lung transplant recipients who had a negative CMV serologic status and a CMV-negative donor (CMV–/–) had better unadjusted survival than any other combination of donor/recipient CMV status, mostly notably compared with CMV-negative recipients who had a CMV-positive donor (“CMV mismatch”). The CMV–/– and CMV-mismatch recipients had unadjusted post-transplant survival of 87% and 84% at 1 year, 61% and 51% at 5 years, and 35% and 28% at 10 years, respectively. Although not adjusted for other factors (e.g., donor or recipient age), these figures highlight the potential adverse effect on long-term survival of selecting a CMV-positive donor for a CMV-negative recipient.
      Figure 7
      Figure 7Kaplan-Meier survival for adult lung transplant recipients by donor (D) and recipient (R) positive (+) and negative (–) cytomegalovirus (CMV) status (transplants: 2004–June 2015). Log-rank test statistic with adjustments for multiple comparisons using Scheffe’s method.
      Multivariable analyses with time to death as the outcome are presented for continuous variables in Table 3 and for categoric variables in Figure 8 (statistically significant risk factors for 1-year mortality) and in Figure 9 (statistically significant risk factors for 5-year mortality). Factors that were consistently and independently associated with increased mortality risk included older donor age, older recipient age, increased recipient creatinine, and higher recipient oxygen requirement (Table 3).
      Table 3Continuous Risk Factors for Mortality by Multivariable Predictor Models
      Variablep-value
      1-year mortality (transplants: January 2003–June 2015)
       Recipient age<0.0001
       Donor age<0.0001
       Recipient creatinine<0.0001
       Total bilirubin<0.0001
       Height difference (donor – recipient)<0.0001
       Recipient oxygen required at rest (liters/min)<0.0001
       Recipient FVC% predicted<0.0001
       Donor BMI0.0007
       Allograft ischemic time0.1829
      5-year mortality (transplants: January 2003–June 2011)
       Recipient age<0.0001
       Donor age<0.0001
       Donor/recipient BMI ratio0.0157
       Height difference (donor – recipient)0.0464
       Recipient oxygen required at rest0.0218
       Allograft ischemic time0.3079
      5-year mortality conditional on survival to 1 year (transplants: January 2003–June 2011)
       Recipient age<0.0001
       Recipient creatinine0.0107
       Donor/recipient BMI ratio0.0239
       Transplant center volume (prior year)<0.0001
       Allograft ischemic time0.0015
      10-year mortality (transplants: January 1999–June 2005)
       Recipient age<0.0001
       Donor age0.0007
       Recipient creatinine0.0098
       Donor/recipient BMI ratio<0.0001
       Recipient oxygen required at rest (liters/min)0.0003
       Donor height0.0316
       Allograft ischemic time0.0156
      BMI, body mass index; FVC, forced vital capacity.
      Figure 8
      Figure 8Statistically significant categoric risk factors for 1-year mortality for adult lung transplant recipients by multivariable analysis (transplants: 2003-June 2015). Hazard ratios, 95% lower and upper confidence limits (LCL, UCL), and p-values were calculated using Cox proportional hazards regression. Continuous risk factors are reported in . CF, cystic fibrosis; CI, confidence interval; CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; HLA, human leukocyte antigen; HTN, hypertension; IIP, idiopathic interstitial pneumonia; IPAH, idiopathic pulmonary arterial hypertension; PH-not IPAH, pulmonary hypertension–not idiopathic pulmonary hypertension; Retx, retransplant.
      Figure 9
      Figure 9Statistically significant risk factors for 5-year mortality for adult lung transplants, multivariable analysis (transplants: 2003-June 2011). Hazard ratios, 95% lower and upper confidence limits (LCL, UCL), and p-values were calculated using Cox proportional hazards regression. Continuous risk factors are reported in . CI, confidence interval; CF, cystic fibrosis; CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; DR, donor-recipient; F, female; IIP, idiopathic interstitial pneumonia; LAM, lymphangioleiomyomatosis; M, male; PH-not IPAH, pulmonary hypertension–not idiopathic pulmonary arterial hypertension; R, recipient; Retx, retransplant.
      Although transplant center volume had an independent association with mortality during the first post-transplant year (eSlides L(a) 104 and 111, respectively) within the primary diagnostic (indication for transplant) groups of COPD and IIP, we did not detect such a relationship in most of the survival models, except for the 5-year survival conditional on survival to 1 year model, where hazard ratios of 5-year mortality were above 1 in both low- and high-volume centers (Table 3, Figure 10, eSlide L(a) 125). These associations do not necessarily imply causation, however. Of the categoric variables, more recent transplant era, fewer human leukocyte antigen mismatches, and a history of hypertension in the donor were all independently associated with lower risk of 1-year mortality (Figure 8). Apart from indications for transplantation other than COPD, independent risk factors for higher 1-year mortality included donor CMV-positive status, donor smoking, donor diabetes, non-ABO identical transplantation, recipient ventilator requirement or hospitalization, and recipient dialysis. The 5-year mortality model (Figure 9) had many risk factors similar to the 1-year mortality model, although a diagnosis of lymphangioleiomyomatosis or cystic fibrosis emerged as factors significantly associated with reduced mortality risk compared with COPD, whereas sex mismatch (female donor to male recipient) transplantation appeared as a significant risk factor for increased mortality risk.
      Figure 10
      Figure 10Hazard ratio for mortality for adult lung transplant recipients within the first 5 years, conditional on survival to 1 year, for center volume (transplants 2003–June 2011; n = 30,404, p< 0.0001). Multivariable analysis was performed using a proportional hazards model censoring all patients at 5 years. Continuous factors were fit using a restricted cubic spline.

      Acute and chronic lung rejection and other transplant-associated morbidities

      Acute rejection remains a significant post-transplant complication, with 28% of recipients with follow-up submitted between 2004 and June 2016 experiencing at least 1 episode of treated acute rejection in the first post-transplant year (eSlide L(a) 38). OB/BOS remains one of the most important post-transplant complications, affecting approximately 10% of patients each year, especially in the first 4 years after transplant (eSlide L(a) 72), with retransplant recipients at an even higher risk (eSlide L(a) 73). Chronic lung allograft dysfunction, which includes OB/BOS and restrictive allograft dysfunction, may have an even greater incidence and prevalence. Freedom from BOS, conditional on survival to 14 days (eSlide L(a) 75) and 1 year (eSlide L(a) 76), was marginally higher in recipients who received induction therapy than in those who did not, although we did not adjust these Kaplan-Meier survival curves for potentially important confounding factors. The prevalence of renal dysfunction and diabetes was high and increased with post-transplant time (eSlides L(a) 67–71) in a fashion similar to previous reports.
      • Yusen R.D.
      • Edwards L.B.
      • Kucheryavaya A.Y.
      • 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.
      • Yusen R.D.
      • Christie J.D.
      • Edwards L.B.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung and heart-lung transplant report—2013; focus theme: age.
      • Yusen R.D.
      • Edwards L.B.
      • Dipchand A.I.
      • et al.
      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.
      • Yusen R.D.
      • Edwards L.B.
      • Kucheryavaya A.Y.
      • et al.
      The Registry of the International Society for Heart and Lung Transplantation: thirty-second official adult lung and heart-lung transplantation report—2015; focus theme: early graft failure.

      Allograft ischemic time

      For 10,883 bilateral and 4,370 adult single primary lung transplants conducted during the era of January 2009 through June 2015, the bilateral lung transplants had a median (interquartile range) allograft ischemic time of 5.5 (2.3) hours and the single lung transplants had a median allograft ischemic time of 4.2 (1.8) hours (Figure 11). Both procedure types had some outliers that had allograft ischemic times of more than 10 hours. For 356 bilateral and 270 single lung retransplants conducted during the same era, bilateral lung retransplants had a median allograft ischemic time of 5.9 (2.7) hours, and single lung retransplants had a median allograft ischemic time of 4.1 (2.0) hours (Figure 11).
      Figure 11
      Figure 11Tukey box plots of allograft ischemic time for unilateral and bilateral adult lung transplants stratified for primary vs retransplant (transplants 2009-June 2015). Boxes demonstrate the median (horizontal line in the box) and the 25th and 75th percentiles (lower and upper box boundaries) or interquartile range; whiskers extend to the case farthest from the box that is within 1.5 box lengths from the edge of the box; outlier cases, between 1.5 and 3 box lengths from the edge of the box, are depicted by diamonds; extreme cases, > 3 box lengths from the edge of the box, are depicted by stars.
      As expected, single lung transplant recipients had a shorter total allograft ischemic time than bilateral recipients. For transplants performed between 2009 and June 2016, 3.3% of single lung recipients and 0.6% of bilateral lung recipients had an allograft ischemic time of < 2 hours. For the 2- to 4-hour allograft ischemic time group, the corresponding percentages were 39.5% (for single lung recipients) and 15% (for bilateral lung recipients). A similar proportion of single lung (45.5%) and bilateral lung (44.0%) transplant recipients had the most common allograft ischemic time duration of 4 to 6 hours, whereas only 11.6% of single compared with 40.4% of bilateral lung recipients had an allograft ischemic time > 6 hours (Figure 11, eSlide L(a) 145).
      Median allograft ischemic times have steadily increased during the past 25 years, from approximately 4 hours in the early 1990s to > 5 hours in the last few years (Figure 12, eSlide L(a) 142). A decrease in the proportion of transplant recipients who had an allograft ischemic time of 2 to < 4 hours and an increase in the proportion of recipients who had an allograft ischemic time of at least 6 hours explains much of this change. The falling proportion of single lung transplants (with relatively shorter allograft ischemic times) over the same period (Figure 1, eSlide L(a) 4) likely explains at least some of these changes.
      Figure 12
      Figure 12Allograft ischemic time distribution for adult lung transplants by year of transplant (transplants: 1988–2015).
      Longer allograft ischemic times occurred in association with older donor but younger recipient age for the 2009 to June 2016 cohort (eSlides L(a) 138 and 140). However, the cohort included only a small number of donors older than 60 years, and these analyses did not adjust for other potentially important factors, including transplant procedure type (single vs bilateral), difficulty of explant, and severity of illness of the recipient.
      In unadjusted analyses, allograft ischemic time showed associations in different directions with donor and recipient age. A long allograft ischemic time of > 6 hours occurred in 30% of recipients with a donor age of 11 to 17 years, 30% of those with a donor age of 18 to 34 years, 32% of those with a donor age of 35 to 49 years, 35% of those with a donor age of 50 to 59 years, 36% those a donor age of 60 to 65 years, and 44% of those with a donor age of at least 66 years (eSlide L(a) 140). In contrast, allograft ischemic time had an inversely proportional relationship to recipient age. A long allograft ischemic time of > 6 hours occurred in 43% of those recipients aged 18 to 34 years, 40% of those aged 35 to 49 years, 34% of those aged 50 to 59 years, 28% of those aged 60 to 65 years, and 22% of those older than 65 years (eSlide L(a) 138). Again, these unadjusted analyses likely reveal trends that have multiple causes.
      For the recent 2009 to June 2016 cohort, we aimed to analyze allograft ischemic time according to geographic location of transplant center (Europe, North America, and elsewhere). Although North America had a limited amount (6.3%) of missing data, we discovered a significant amount of missing data for transplants reported from Europe (74.8%) and from other geographic regions (23.8%). Keeping these limitations in mind, only 1% of recipients in each region had an allograft ischemic time <2 hours (Figure 13, eSlide L(a) 143). The North American and non-North American, non-European lung transplant recipients had similar proportions in the allograft ischemic time categories: 24% and 26% of recipients had an allograft ischemic time of 2 to 4 hours, 46% and 43% had an allograft ischemic time of 4 to 6 hours, and 28% and 29% had an allograft ischemic time of > 6 hours, respectively. In contrast to these regions, and based on potentially biased reporting, only 9% of European recipients had an allograft ischemic time of 2 to 4 hours, whereas 35% had an allograft ischemic time of 4 to 6 hours, and 55% had an allograft ischemic time of > 6 hours (Figure 13, eSlide L(a) 143).
      Figure 13
      Figure 13Allograft ischemic time distribution for adult lung transplants by location (transplants: 2009–June 2016). Transplants with unknown allograft ischemic time are excluded from this tabulation: 74.8% of transplants from Europe, 6.3% from North America, and 23.8% from other locations had missing allograft ischemic time.
      Allograft ischemic time did not show any clinically meaningful trends among the primary diagnostic indications for transplant (eSlide L(a) 137) among recipients stratified by requirement for ventilatory support (eSlide L(a) 139), among donors stratified by cause of death (eSlide L(a) 141), or among centers stratified by volume (eSlide L(a) 144).
      For lung transplants that occurred in the recent era of January 2009 through June 2015, recipients who had allograft ischemic time of > 6 hours had a lower Kaplan-Meier unadjusted 30-day survival than the other allograft ischemic time groups (Figure 14, eSlide L(a) 146), although statistical significance was only seen between the 2 groups that had the longest allograft ischemic times. However, these differences were not sustained in the long-term. In fact, survival appeared similar among the 4 groups through approximately 4 years after transplant, after which lung transplant recipients who had an allograft ischemic time >6 hours had a higher Kaplan-Meier unadjusted survival compared with the 2- to < 4-hour allograft ischemic time group.
      Figure 14
      Figure 14Kaplan-Meier survival to 30 days for adult lung transplant recipients by allograft ischemic time (transplants: 2009–June 2015). Log-rank test statistic with adjustments for multiple comparisons using Scheffe’s method.
      Meanwhile, the other group-wise comparisons were not significantly different (Figure 15, eSlide L(a) 147). The longer allograft ischemic time group also had a higher unadjusted freedom from BOS compared with the 4- to <6-hour and the 2- to <4-hour allograft ischemic time groups (Figure 16, eSlide L(a) 149). Although the multivariable survival models did not show an independent association between allograft ischemic time and 1- or 5-year mortality (Table 3), they did show an independent association of longer allograft ischemic time with lower mortality in the 5-year survival model that was conditional on survival to 1 year and in the 10-year mortality model. We did not adjust the Kaplan-Meier curves for important factors such as transplant type (i.e., single vs bilateral), but the multivariable models did adjust for a number important factors (Table 3). The identification of an association of the longer ischemic time with better outcome was unexpected. These findings should be interpreted with caution because of missing ischemic time data for many European transplant recipients, lack of model adjustment for unmeasured (or not collected) potential confounders, and the current lack of external validation.
      Figure 15
      Figure 15Kaplan-Meier survival for adult lung transplant recipients by allograft ischemic time (transplants: 2009–June 2015). Log-rank test statistic with adjustments for multiple comparisons using Scheffe’s method. The results of the log-rank test should be interpreted with caution when curves cross.
      Figure 16
      Figure 16Kaplan-Meier freedom from bronchiolitis obliterans syndrome (BOS) for adult lung transplant recipients by allograft ischemic time (transplants: 2009–June 2015). Log-rank test statistic with adjustments for multiple comparisons using Scheffe’s method.
      Owing to a lack of standardized data collection of primary graft dysfunction variables by data collectives, we did not have the opportunity to analyze the relationship of allograft ischemic time to primary graft dysfunction. Regarding another early postoperative outcome, again not adjusted for other factors, we found an association between allograft ischemic time and episodes of treated acute rejection (defined as having at least 1 acute rejection episode that was treated with an anti-rejection agent or having been hospitalized for rejection) in the first year after transplant, where each longer allograft ischemic time group had a greater proportion of recipients that experienced treated rejection (Figure 17, eSlide L(a) 148).
      Figure 17
      Figure 17Percentage of adult lung transplant recipients experiencing treated rejection between discharge and the 1-year follow-up by allograft ischemic time (transplants: 2009–June 2015).

      Heart-lung transplantation

      Centers and transplant activity

      The annual reported number of heart-lung transplants has continued its downward trend during the past 25 years, having peaked at 225 transplants in 1989 and 1990. In 2015, only 38 transplants were reported to the Registry (Figure 18, eSlide HL(a) 4). Eighty-six centers reported at least 1 heart-lung transplant performed between 2009 and June 2016 to the Registry, with 54 (63%) of these centers reporting an average of 1 procedure per year (eSlide HL(a) 5).
      Figure 18
      Figure 18Number of adult heart–lung transplants reported to the International Society for Heart and Lung Transplantation Registry by year (transplants: 1982–2015).

      Indications and other recipient characteristics

      Indications for heart-lung transplantation for the 3,213 transplants performed between 1982 and June 2016 are provided in Table 4. The 2016 Registry report provided an in-depth description and analysis of primary diagnostic indication for heart-lung transplant.
      • Yusen R.D.
      • Edwards L.B.
      • Dipchand A.I.
      • et al.
      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.
      Pulmonary hypertension—either idiopathic or non-idiopathic—has remained the indication for transplantation in approximately 66% of recipients for the past 2 decades. In contrast, cystic fibrosis has become an increasingly rare indication, whereas a small but increasing number of transplant recipients had a primary diagnosis of idiopathic interstitial pneumonia (Figure 19, eSlides HL(a) 8 and HL(a) 9).
      Table 4Primary Indications
      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 misclassification may occur.
      for Adult Heart-Lung Transplants (Transplants: January 1982—June 2016)
      No. (%)
      Diagnosis
      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 misclassification may occur.
      (N = 3,213)
      COPD204 (6.3)
       Without A1ATD141 (4.4)
       With A1ATD63 (2.0)
      ILD
      Categories may include other types of IIP and non-IIP.8
      160 (5.0)
       IIP
      Likely includes other types of World Health Organization Group 1 PAH.9
      113 (3.5)
       ILD-not IIP
      Likely includes other types of World Health Organization Group 1 PAH.9
      47 (1.5)
      Bronchiectasis495 (15.4)
       CF
      Presumably associated with bronchiectasis.
      462 (14.4)
       Bronchiectasis not associated with CF33 (1.0)
      PAH2,157 (67.1)
       IPAH953 (29.7)
       PH-not IPAH1,204 (37.5)
      Miscellaneous155 (4.8)
       Sarcoidosis58 (1.8)
       OB (not retransplant)23 (0.7)
       Other74 (2.3)
      Retransplant
      Retransplant includes those with a previously reported lung or heart-lung transplant or a retransplant diagnosis.4
      42 (1.3)
      A1ATD, α-1-anti-trypsin deficiency; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; IIP, idiopathic interstitial pneumonia; ILD, interstitial lung disease; IPAH, idiopathic pulmonary arterial hypertension; OB, obliterative bronchiolitis; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension.
      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 misclassification may occur.
      b Categories may include other types of IIP and non-IIP.
      • Travis W.D.
      • Costabel U.
      • Hansell D.M.
      • et al.
      An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
      c Likely includes other types of World Health Organization Group 1 PAH.
      • Simonneau G.
      • Robbins I.M.
      • Beghetti M.
      • et al.
      Updated clinical classification of pulmonary hypertension.
      d Presumably associated with bronchiectasis.
      e Retransplant includes those with a previously reported lung or heart-lung transplant or a retransplant diagnosis.
      • Yusen R.D.
      • Edwards L.B.
      • Kucheryavaya A.Y.
      • 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.
      Figure 19
      Figure 19Indications for adult heart–lung transplantation (% of all transplants for that year) by year of transplant (transplants: 1990–2015). Because only major indications are shown, the sum of the percentages for each year is less than 100%. CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; IIP, idiopathic interstitial pneumonia; IPAH, idiopathic pulmonary arterial hypertension; PH-not IPAH, pulmonary hypertension-not idiopathic pulmonary arterial hypertension.
      Although most heart-lung transplant recipients were aged younger than 50 years at the time of transplant, a significant proportion of patients in Europe and North America were not. Of the heart-lung transplants performed between June 2004 and June 2016, 21% of European center recipients and 32% of North American recipients were aged 50 years or older at the time of transplant (eSlide HL(a) 11). Centers uncommonly performed heart-lung transplantation in recipients who were aged 60 years or older at the time of transplant, although this group comprised 8% of North American heart-lung transplant recipients (eSlide HL(a) 11).

      Survival

      Heart-lung transplantation has continued to have a high mortality risk in the early post-transplant period but a lower risk in the long-term. For heart-lung transplants reported from 1982 to June 2015, recipients had median survival of only 3.3 years. However, recipients who survived the first post-transplant year had a median survival of 10.3 years (eSlide HL(a) 15), with this conditional survival improving in the most recent 2 of 3 eras (eSlide HL(a) 17).

      Causes of death

      Causes of death for adult heart-lung transplant recipients (Table 5) differ slightly from those for adult lung transplant recipients (Table 2). Adult lung transplant recipients were more likely to die of BOS and malignancy, whereas heart-lung transplant recipients were more likely to die of infection and cardiovascular events.
      Table 5Known Causes of Death for Adult Heart-lung Transplant Recipients
      Includes primary transplants and retransplants.
      (Deaths: January 1992—June 2016)
      0–30 days31 days–1 year>1–3 years>3–5 years>5 years
      Cause of death
      Data are expressed as number (%). Data in parentheses indicate percentage of deaths out of all deaths with known cause in the respective time period.
      ,
      Some misclassification may occur 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 OB/BOS or other causes late after transplant.
      (n = 472)(n = 360)(n = 294)(n = 175)(n = 535)
      OB/BOS014 (3.9)69 (23.5)38 (21.7)110 (20.6)
      Graft failure127 (26.9)76 (21.1)44 (15.0)32 (18.3)78 (14.6)
      Acute rejection7 (1.5)6 (1.7)5 (1.7)1 (0.6)3 (0.6)
      Infection (CMV and non-CMV)80 (16.9)128 (35.6)86 (29.3)46 (26.3)116 (21.7)
      Malignancy
       Non-lymphoma1 (0.2)8 (2.2)13 (4.4)7 (4.0)43 (8.0)
       Lymphoma07 (1.9)12 (4.1)8 (4.6)11 (2.1)
      Cardiovascular39 (8.3)15 (4.2)22 (7.5)18 (10.3)53 (9.9)
      Technical110 (23.3)12 (3.3)3 (1.0)3 (1.7)7 (1.3)
      Multiple organ failure51 (10.8)54 (15.0)15 (5.1)7 (4.0)36 (6.7)
      Other57 (12.1)40 (11.1)25 (8.5)15 (8.6)78 (14.6)
      BOS, bronchiolitis obliterans syndrome; CMV, cytomegalovirus; OB, obliterative bronchiolitis.
      a Includes primary transplants and retransplants.
      b Data are expressed as number (%). Data in parentheses indicate percentage of deaths out of all deaths with known cause in the respective time period.
      c Some misclassification may occur 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 OB/BOS or other causes late after transplant.

      Heart-lung transplant immunosuppression and rejection

      In contrast to trends in lung transplantation, heart-lung transplant recipients have lower rates of induction use (approximately 40%–70% of recipients), which have not significantly increased during the past decade (eSlide HL(a) 27). Similar to the trends in lung transplantation, heart-lung recipients most commonly receive tacrolimus and mycophenolate mofetil for immunosuppression (eSlide HL(a) 28). Cardiac allograft vasculopathy and BOS both commonly occur after heart-lung transplantation, although more patients remain free of cardiac allograft vasculopathy than BOS (Figure 20, eSlide HL(a) 32). Compared with lung transplant recipients, heart-lung transplant recipients have greater freedom from BOS, with slightly less than 10% experiencing this complication each year, resulting in 57% of heart-lung transplant recipients remaining free from BOS at 5 years (Figure 20, eSlide HL(a) 32) compared with 50% of lung transplant recipients (eSlide L(a) 72).
      Figure 20
      Figure 20Kaplan-Meier freedom from cardiac allograft vasculopathy (CAV) and freedom from bronchiolitis obliterans syndrome (BOS), censoring for death, for adult heart-lung transplant recipients: (transplants: 1994–June 2015).

      Complications, morbidities, and survival

      Table 6 reports cumulative morbidity rates for survivors of adult heart-lung transplantation. Renal dysfunction commonly occurred, although chronic dialysis treatment was reported in only 4.4% and 3.0% of survivors at 1 and 5 years after transplant. Recipients showed a marked increase in the prevalence of diabetes in the years after transplant, with increases from 17.7% at 1 year to 28.4% at 5 years. Adult heart-lung transplant surviving recipients had a 31.5% prevalence of BOS at 5 years compared with 41.6% for adult lung transplant recipients.
      Table 6Cumulative Morbidity Rates in Adult Heart-lung Transplant
      Combined group of primary transplants and retransplants.
      Survivors (Transplants: January 1994–June 2015)
      Within 1 year
      Percentage of patients with known responses that experienced various morbidities as reported on forms at or before the 1-year and the 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 with known responseWithin 5 Years
      Percentage of patients with known responses that experienced various morbidities as reported on forms at or before the 1-year and the 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 with known response
      Outcome(%)(No.)(%)(No.)
      Renal dysfunction20.050043.0237
       Abnormal creatinine ≤ 2.5 mg/dl12.027.8
       Creatinine > 2.5 mg/dl3.411.0
       Chronic dialysis4.43.0
       Renal transplant0.21.3
      Diabetes mellitus17.752128.4264
      Coronary artery vasculopathy2.94086.8132
      Bronchiolitis obliterans syndrome7.547831.5219
      a Combined group of primary transplants and retransplants.
      b Percentage of patients with known responses that experienced various morbidities as reported on forms at or before the 1-year and the 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.
      Multivariable analyses only detected a few factors that had an association with death after heart-lung transplantation. For those who received transplants from 1998 to June 2015, a recipient history of diabetes and pre-transplant ventilatory support and transplantation in a center with low annual transplant volume were associated with an increased risk of death. Centers with a volume of at least 25 transplants in the previous year had a lower risk of death than centers with a lower volume (eSlide HL(a) 42).

      Allograft ischemic time

      Allograft ischemic times for heart-lung transplantation have varied during the past 3 decades. Heart-lung transplant recipients had a median allograft ischemic time of only 2 to 3 hours in the 1980s, which increased to approximately 4 hours in the 1990s and early 2000s, before falling again to 3 to 4 hours in the past decade (Figure 21, eSlide HL(a) 49).
      Figure 21
      Figure 21Allograft ischemic time distribution for adult heart-lung transplants by year of transplant (transplants: 1986–2015).
      Unlike the findings in lung transplantation, heart-lung transplant allograft ischemic time did not show a significant association with donor or recipient age (eSlides HL 45 and HL 47) or transplant center geographic location (Europe, North America, or other; Figure 22, eSlide HL(a) 50), although European centers reported more variability in allograft ischemic time compared with other regions. Similar to the lung transplant data, considerable variation in data missingness occurred by region, with ischemic times reported for 90% of North American recipients, 59% of recipients from other geographic areas, but for only 11% of European recipients.
      Figure 22
      Figure 22Allograft ischemic time distribution for adult heart-lung transplants by location (transplants: 2004–June 2016).
      Allograft ischemic time did not predict short- or long-term survival after heart-lung transplant, although statistical power to detect differences was limited because of the small number of recipients in each of the allograft ischemic time groups, particularly for the very short (<2 hours) and the very long (> 6 hours) allograft ischemic time groups (Figure 23, eSlide HL(a) 52, and Figure 24, eSlide HL(a) 53).
      Figure 23
      Figure 23Kaplan-Meier survival to 30 days for adult heart-lung transplant recipients by allograft ischemic time (transplants: 1998–June 2015). Log-rank test statistic with adjustments for multiple comparisons using Scheffe’s method.
      Figure 24
      Figure 24Kaplan-Meier survival for adult heart-lung transplant recipients by allograft ischemic time (transplants: 1998–June 2015). Log-rank test statistic with adjustments for multiple comparisons using Scheffe’s method.

      Conclusions

      The introduction of novel techniques (e.g., lung and heart transplantation using organs donated after circulatory death
      • Levvey B.J.
      • Harkess M.
      • Hopkins P.
      • et al.
      Excellent clinical outcomes from a national donation-after-determination-of-cardiac-death lung transplant collaborative.
      • Dhital K.K.
      • Iyer A.
      • Connellan M.
      • et al.
      Adult heart transplantation with distant procurement and ex-vivo preservation of donor hearts after circulatory death: a case series.
      ) and of technologies (ex vivo organ perfusion
      • Simonneau G.
      • Robbins I.M.
      • Beghetti M.
      • et al.
      Updated clinical classification of pulmonary hypertension.
      • Cypel M.
      • Yeung J.C.
      • Liu M.
      • et al.
      Normothermic ex vivo lung perfusion in clinical lung transplantation.
      ) will inevitably affect cold and warm allograft ischemic times for a small but increasing number of cardiothoracic transplant recipients. Given these changes in practice, we reviewed the current Registry data to determine characteristics of allograft ischemic time for adult lung and heart-lung transplantation, historical trends, and ischemic time associations with donor and recipient factors and post-transplant outcomes. Thanks to the data reporting efforts of the large number of participating transplant centers and collectives worldwide, this Registry report provides comprehensive and current information regarding developments and challenges in adult lung and heart-lung transplantation, with a particular focus this year on allograft ischemic time.
      In general, previously noted trends in lung and heart-lung transplantation have continued. The increase in the number of lung transplants reported to the Registry has plateaued in the past 3 years, while the number of reported heart-lung transplants has continued to fall. A notable departure from previous trends is the failure of medium-term adult lung transplant survival to continue to improve era-upon-era. Multiple causal factors may explain this change, such as temporal changes in recipient age and health status, transplant center–specific factors, and organ allocation factors. Nevertheless, this trend warrants continued observation and further investigation in the coming years.
      We identified interesting associations between allograft ischemic time for adult lung transplantation and donor and recipient age, post-transplant survival, acute rejection, and freedom from BOS, inviting further investigation and analysis of the observed associations. We also identified an association between transplant center geographic location and allograft ischemic time, but we could not make strong conclusions regarding these associations due to the regionally uneven submission of allograft ischemic time data. Also, the absence of allograft ischemic time data for the first lung implanted during bilateral lung transplantation restricted our ability to analyze the effect of allograft ischemic time on outcomes for single vs bilateral lung transplantation. Despite these limitations, this Registry report provides a detailed description and analysis of allograft ischemic times and trends around the world and identifies important opportunities to improve data reporting. We hope this report will also stimulate further research into the effect of allograft ischemic time on lung and heart-lung transplant outcomes, particularly as historical allograft ischemic time norms change dramatically with the advent of new technologies.

      Disclosure statement

      D.C. received travel support from Astellas Pharma, Inc. and serves as a consultant and speaker for Roche Ltd. L.G.L. received research grant support to his institution from Novartis Inc. and Abbott Inc. J.W.R. and J.S. serve as consultants for Medtronic, Inc. None of the other authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.

      Supplementary materials

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