Double- and Single-Lung Transplantation: An Analysis of Twenty Years of OPTN/UNOS Registry Data

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1 1 CHAPTER 1 Double- and Single-Lung Transplantation: An Analysis of Twenty Years of OPT/UOS Registry Data Junchao Cai Terasaki Foundation Laboratory, Los Angeles, CA, USA The number of lung transplants steadily increased in the United States within past 2 decades. The annual numbers of lung transplants exceeded 1,4 in 25 and 26. The percentage of patients, who experienced acute rejection within the first posttransplant year, significantly dropped from more than 9% during the199s to less than 4% in recent years. Short- and long-term graft survival rates for both double- and single-lung transplants significantly improved in recent years. PATIETS AD METHODS Between 1/1/1987 and -11/2/27, 7,962 double-lung transplants, 4,325 left-lung transplants, and 4,114 right-lung transplants were reported to the UOS registry ( Statistical analyses presented in this chapter include the entire cohort of double- and single-lung transplant recipients. Survival rates were calculated using Kaplan-Meier methods. Statistical significance was determined by the log-rank test for comparison of survival curves. Waiting List According to the UOS national data reports, as of January 4, 28, 2,237 patients were on the waiting list. Among them, 1,16 patients were in the 5-64 age group and 53 patients were in age group (Figure 1). When all the waiting patients are grouped by their original diseases, COPD, IPF, CF, PPH, ATD and Sarcoidosis were the top 6 major diseases which represented 78% of patients (Figure 2). Figure 1. Current US lung transplant waiting list by patient age. OPT/UOS LUG REGISTRY RESULTS Major Lung Transplant Centers As of October 31, 27, a total of 11 US transplant centers reported at least one lung transplant, while 17 US centers performed living donor singlelung transplants (Table 1). About 76% of deceased donor lung transplants were performed by the top 3 centers; while more than 5% of living donor lung transplants were performed in 2 Los Angeles hospitals. umber of patients COPD IPF CF PPH ATD Sarcoidosis Others Figure 2. Current US lung transplant waiting list by patient original diseases. Clinical Transplants 27, Terasaki Foundation Laboratory, Los Angeles, California

2 2 CAI Table 1. Major lung transplant centers in the US. Rank Centers Donor Type Percent Percent (accumulated) Largest Deceased Donor Lung Transplant Centers Deceased all centers (11) 16,13 1 PAPT-TX1 Univ of Pittsburgh Med Ctr MOBH-TX1 Barnes-Jewish Hospital CDU-TX1 Duke University Medical Center OHCC-TX1 Cleveland Clinic Foundation MUM-TX1 Univ. of Minnesota Medical Center PAUP-TX1 The Hosp of the Univ of PA ILLU-TX1 Loyola Univ Med Center YCP-TX1 The Presbyterian Hosp in Y City ALUA-TX1 Univ of Alabama Hospital WAUW-TX1 Univ of Washington Med Ctr IIM-TX1 Clarian Health-Methodist/IU/Riley COUC-TX1 University of Colorado Hospital/HSC MIUM-TX1 Univ of Michigan Med Ctr CAUC-TX1 UCLA Medical Center FLUF-TX1 Shands Hosp at Univ of Fl WIUW-TX1 Univ of Wisconsin Hosp and Clinics VAUV-TX1 Univ of Virginia HSC CASD-TX1 UCSD Medical Center TXMH-TX1 The Methodist Hospital CASU-TX1 Stanford Univ Med Ctr CMH-TX1 UC Hospitals TXBC-TX1 University of Texas Health Science Center MAPB-TX1 Brigham and Womens Hosp MOCH-TX1 St. Louis Childrens Hospital CASF-TX1 Univ of CA San Francisco Med Ctr CAUH-TX1 USC University Hospital TVU-TX1 Vanderbilt Univ Med Ctr VAFH-TX1 Inova Fairfax Hosp TXTX-TX1 Baylor University Medical Center GAEM-TX1 Emory Univ Hospital ALL 17 Living Donor Lung Transplant Centers Living all 17 centers CAUH-TX1 USC University Hospital CACL-TX1 Childrens Hospital Los Angeles MOCH-TX1 St. Louis Childrens Hospital MAMG-TX1 Massachusetts General Hospital MUM-TX1 Univ. of Minnesota Medical Center CMH-TX1 UC Hospitals CDU-TX1 Duke University Medical Center PAPT-TX1 Univ of Pittsburgh Med Ctr CASD-TX1 UCSD Medical Center VAUV-TX1 Univ of Virginia HSC CASU-TX1 Stanford Univ Med Ctr PACP-TX1 Childrens Hosp of Philadelphia MAPB-TX1 Brigham and Womens Hosp MDJH-TX1 Johns Hopkins Hospital PACH-TX1 Childrens Hospital of Pittsburgh MACH-TX1 Childrens Hospital Boston TLB-TX1 Le Bonheur Childrens Med Ctr During the time period of 1/1/1988~1/31/27, a total of 16,378 lung transplants (16,13 deceased donor, 248 living donor) were performed in 12 US trasplant centers. About 76% of deceased donor lung transplantation were performed by the top 3 centers; while more than 5% of living donor lung transplantation were performed in two hospitals in Los Angeles.

3 3 Table 2. Major indications for lung transplantation in the US. Double Left Right Indications % Indications % Indications % CF 2, COPD 2, COPD 2, COPD 1, IPF 1, IPF IPF 1, ATD ATD PPH Other, Specify PPH ATD CF CF Bronchiectasis PF-Others Sarcoidosis Sarcoidosis Sarcoidosis Other, Specify Other, Specify PPH PF-Others PF-Others GF-OB GF-OB GF-OB LAM 23.5 ES(ASD) 28.7 CF=Cystic fibrosis; COPD=COPD/Emphysema; IPF=Idiopathic pulmonary fibrosis; PPH=Primary pulmonary hypertension; ATD=Alpha antitrypsin deficiency; PF-Others=Pulmonary fibrosis-other specify cause; GF-OB=Lung retransplant/graft Failure: Obliterative bronchiolitis; LAM=Lymphangioleiomyomatosis; ES(ASD)=Eisenmenger s syn: atrial septal defect Major Indications for Lung Transplantation The major indications for double- and single- (left or right) lung transplants differed in their rank order (Table 2). For double-lung transplants, CF (3.1%), COPD (21.4%), and IPF (13%) were the top 3 indications; while for single lung transplantation, COPD (46.3% L, 52.7% R), IPF (28.1% L, 2.8% R) and ATD (7.6% L, 8.% R) were the 3 major indications. It is notable, that patients with an original diagnosis of COPD alone accounts for almost 5% of all single-lung transplant recipients. Annual Case umbers The annual numbers of lung transplants, and especially double-lung transplants, steadily increased during the past 2 decades (Figure 3). In 1993, the number of double-lung (D) transplants first exceeded the number of either left- (L) or right (R)-lung transplants. Since 22, the annual number of double-lung transplants has exceeded the sum of left- and right-lung transplants. The annual increase in lung transplants was mainly due to the increase in double-lung transplants. OPT/UOS LUG REGISTRY Figure 3. Annual trends in US lung transplantation.

4 4 CAI A Graft survival (%) Double 7,74 Left 4,185 Right 3,971 p<.1 B p=.3473 Figure 4. A. Ten-year graft survival among primary lung transplant recipients. B. Ten-year graft survival among repeat lung transplant recipients. Overall Graft Survival Rates When the entire cohort of lung transplant patients was included in the analysis of first transplant recipients, graft survival rates differed significantly between double- and single-lung transplant recipients and also between right- and left-lung transplant recipients (right>left, p<.1) (Figure 4A). However these differences were not significant among regrafted patients (Figure 4B). Graft survival (%) Double , , ,549 p< Left 1,87 1,177 1,799 p< Years Posttrantplant Right 1,77 1,129 1,661 p< Figure 5. Three-year graft survival for double lung, left lung, and right lung recipients by transplant era. Graft Survival Rates by Eras To analyze the transplant year effect on graft survival, lung transplant recipients were grouped based on their year of transplantation: , , and Three-year graft survival analysis demonstrated that patients who received either double- or single-lung transplants during the most recent era had better graft survival rates than those who were transplanted in earlier eras. The improvement of long-term graft survival seems mainly due to improved one-year survival, more precisely, due to the decreased graft failure

5 5 Graft survival (%) HLA MM -3 1, , ,173 Double 6 1,234 p= ,148 Left 676 p= ,141 Right 69 p=.2772 Figure 6. Ten-year graft survival among double lung, left lung, and right lung transplant recipients by HLA mismatch. rate within the first 2-3 months (Figure 5). Graft Survival and HLA Mismatches The average HLA mismatch level was 4.5±1.1 for all lung transplant recipients, and there was no difference between different types of lung transplantation (data not shown). To see the effect of HLA mismatch on long-term graft survival, lung transplant recipients were grouped based on HLA-mismatch levels: -3, 4, 5 and 6 mismatches. Figure 6 shows a negative association between HLA mismatch and 1-year graft survival and this negative effect of mismatch on graft survival is statistically significant in both double- and left-lung transplants. Graft Survival and First Year Rejection Episodes As shown in Figure 7, before 1997 more than 8% of lung transplant recipients reportedly had drug-treated rejection during the first posttransplant year. The first year rejection rates significantly decreased to less than 7% in 1998 and continued to drop over the past 1 years. It is clear that, for either double- or single-lung transplant recipients, patients who experienced drug-treated rejection with the first posttransplant year had significantly poorer long-term graft survival compared to those without rejection (Figure 8). Graft Survival and Recipient Original Diseases OPT/UOS LUG REGISTRY Figure 7. Annual incidence of treated rejection within the first posttransplant year. As we reported in 26, the top 5 diseases leading to lung transplantation included COPD, IPF, CF, ATD, and PPH (1). Graft survival rates for double-, left- and right-lung transplant recipients were compared in different cohorts grouped by original diseases. As shown in Figure 9, except for CF patients with mostly living donor single-lung transplants, double-lung transplant recipients almost always had better survival than those with either left- or right-lung transplants. For COPD, ATD, and PPH patients, rightlung transplants had a significantly higher graft survival rate than left-lung transplants. However, left-lung transplants had better survival rates than right-lung transplants among CF patients. Among IPF and other original diseases patients, there was no significant difference between left- and right-lung transplants.

6 6 CAI Graft survival (%) Rejection o 2,37 Yes Double 1,663 p< Left 977 p=.42 Years Posttrantplant 787 Right 953 p=.13 Figure 8. Ten-year graft survival among double lung, left lung, and right lung transplant recipients by first year treated rejection. Graft Survival (%) Graft Survival (%) COPD Double 1,697 Left 1,996 Right 2,158 p<.1 ATD Double 531 Left 329 Right 327 p<.1 Double 1,32 Left 1,211 Right 849 p= PPH Double 538 Left 81 Right 144 IPF p=.469 Double 2,394 Left 18 Right 99 CF p=.138 Double 1,517 Left 462 Right 396 others p=.166 Figure 9. Ten-year graft survival among lung transplant recipients by original disease.

7 7 Figure 1. Ten-year graft survival among female lung transplant recipients by original disease. Interestingly, when recipients were further subgrouped by patient gender, the survival differences between left- and right-lung transplants seemed to be gender related. Among female single-lung recipients (Figure 1), right-lung transplants had higher graft survival than left-lung for COPD, ATD, and other diseases; while for IPF, CF, and PPH patients, the differences were not significant. Among male single-lung recipients (Figure 11), CF patients had better graft survival when they received a left lung; while PPH patients had higher graft survival when they received a right lung. There was no statistically significant difference between left and right lung transplantation for male recipients when their original diseases were COPD, IPF, ATD, or others. OPT/UOS LUG REGISTRY

8 8 CAI Graft Survival (%) Graft Survival (%) CF Double 1,258 Left 36 Right 37 p=.71 IPF Double 668 Left 786 Right 573 p=.6643 PPH Double 165 Left 24 Right 41 p=.33 ATD Double 341 Left 175 Right 21 p=.4363 Double 882 Left 99 Right 954 p=.489 Double 69 Left 191 Right COPD others 166 p=.272 Figure 11. Ten-year graft survival among male lung transplant recipients by original disease. SUMMARY 1. Within the past 2 decades, the annual number of lung transplants, especially double-lung transplants, has steadily increased every year and exceeded 1,4 in the last 2 years. 2. Overall 1-, 5-, and 1-year graft survival rates for double-lung transplant recipients were 79.5%, 5.6%, and 3.4% respectively; those for left-lung transplant recipients were 76.%, 41.8%, and 17.1%; and for right-lung transplant recipients were 78.3%, 44.8%, and 19.2%. 3. The improvement in long-term graft survival in the most recent transplant era was mainly due to improved one-year survival, more precisely, due to the increased early outcome within the first 2-3 months after transplantation. 4. A negative association between HLA mismatch and graft survival is statistically significant in both double and left-lung transplants. 5. Female COPD and ATD single-lung recipients had high long-term graft survival when they received right-lung transplants. While for male single-lung recipients, CF patients had better graft survival when they received left lung transplants; but PPH patients had higher graft survival when receiving right-lung transplants. This association between recipient gender and/or different original diseases and graft survival requires further investigation. 1. Cai J, Mao Q, Ozawa M, Terasaki PI. Lung transplantation in the United States In: Cecka JM, Terasaki PI, Eds. Clinical Transplants 25. Los Angeles, UCLA Immunogenetics Center 25; REFERECES