A look Inside A Surgeon’s Perspective Hassan Nemeh, MD Henry Ford Hospital Michigan Society of Respiratory Care Spring Conference 2016 Historical background

Alexis Carrel 1905

Reported on and lung transplant in a cat model Historical background

Vladimir Demikhov

Reported on 20 different techniques of heart and heart- lung transplant in 1950 Historical background

James Hardy, MD

First human lung transplant 1964 by Hardy Historical background

• Fritz Derom achieved a 10 months survival after lung transplant in a patient with pulmonary silicosis in 1971. Historical background

• started a clinical trial in heart-lung transplant in 1981 after success in primate model in the lab Historical background

• The Toronto group headed by Joel Cooper established lung transplant as we know it today Adult Lung Transplants Number of Transplants by Year and Procedure Type

4000 3893 3745 3750 3500 Bilateral/Double Lung 3450 3177

3000 Single Lung 28382901 2699 2481 2500 2129 2000 19011934 1711 1630 1483 14171440 1500 12961301 1160 1055 1000 874 Number of Transplants 664 500 384 160 5 6 32 69 0

NOTE: This figure includes only the adult lung transplants that are reported to the ISHLT Transplant Registry. As such, this should not be construed as representing changes in the 2015 number of adult lung transplants performed worldwide.

JHLT.JHLT. 20152014 Oct;Oct; 34(10):33(10): 12641009--12771024 Indications

• Cystic fibrosis FEV1 <30%, or clinical worsening

• COPD FEV1<25% or PCO2 >55 with pul. HTN

• IPF Symptomatic, VC <60-70%, DLCO <50-60%

• PPH NYHA class III or IV on vasodilator

• Eisenmenger’s NYHA class IIIorIV Adult Lung Transplants Indications (Transplants: January 1995 – June 2014)

Diagnosis SLT (N=16,226) BLT (N=29,457) TOTAL (N=45,683) COPD/Emphysema 6,826 (42.1%) 7,856 (26.7%) 14,682 (32.1%) Idiopathic Pulmonary Fibrosis 5,561 (34.3%) 5,442 (18.5%) 11,003 (24.1%) Cystic Fibrosis 228 (1.4%) 7,191 (24.4%) 7,419 (16.2%) Alpha-1 792 (4.9%) 1,667 (5.7%) 2,459 (5.4%) Idiopathic Pulmonary Arterial Hypertension 91 (0.6%) 1,250 (4.2%) 1,341 (2.9%) Pulmonary Fibrosis, Other 758 (4.7%) 1,125 (3.8%) 1,883 (4.1%) Bronchiectasis 65 (0.4%) 1,167 (4.0%) 1,232 (2.7%) Sarcoidosis 301 (1.9%) 857 (2.9%) 1,158 (2.5%) Retransplant: Obliterative Bronchiolitis 338 (2.1%) 440 (1.5%) 778 (1.7%) Connective Tissue Disease 200 (1.2%) 481 (1.6%) 681 (1.5%) Obliterative Bronchiolitis (Not Retransplant) 110 (0.7%) 381 (1.3%) 491 (1.1%) LAM 142 (0.9%) 330 (1.1%) 472 (1.0%) Retransplant: Not Obliterative Bronchiolitis 210 (1.3%) 246 (0.8%) 456 (1.0%) Congenital Heart Disease 93 (0.6%) 333 (1.1%) 426 (0.9%) Cancer 7 (0.0%) 30 (0.1%) 37 (0.1%) Other 504 (3.1%) 661 (2.2%) 1,165 (2.6%)

For some retransplants, a diagnosis other than retransplant was 2015 reported, so the total number and percentage of retransplants JHLT.JHLT. 20152014 Oct;Oct; 34(10):33(10): 12641009--12771024 may be greater. Adult Lung Transplants Procedure Type within Indication, by Year

Bilateral/Double Lung Transplant Single Lung Transplant 100% 90% 80% 70% 60% 50% 40%

% of Transplants 30% 20% 10% 0% 1999 2001 2003 2005 2007 2009 2011 2013 1999 2001 2003 2005 2007 2009 2011 2013 1999 2001 2003 2005 2007 2009 2011 2013 1999 2001 2003 2005 2007 2009 2011 2013 AT Def COPD IPF IPAH

2015

JHLT.JHLT. 20152014 Oct;Oct; 34(10):33(10): 12641009--12771024 Adult Lung Transplants Major Indications by Year (Number) 3,500 CF IPF COPD Alpha-1 IPAH Retx 3,000

2,500

2,000

1,500

Number of Transplants 1,000

500

0

Transplant Year For some retransplants, a diagnosis other than 2015 retransplant was reported, so the total percentage of retransplants may be greater. JHLT.JHLT. 20152014 Oct;Oct; 34(10):33(10): 12641009--12771024

Adult Lung Transplants Kaplan-Meier Survival by Procedure Type for Primary Transplant Recipients (Transplants: January 1990 – June 2013) 100 Median survival (years): Bilateral/Double lung: 7.1; Conditional=9.7 Single lung: 4.5; Conditional=6.4 80

60 p < 0.0001

40 Survival (%) Survival

20 Bilateral/Double Lung (N=28,135) Single Lung (N=17,099) 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Years 2015

JHLT.JHLT. 20152014 Oct;Oct; 34(10):33(10): 12641009--12771024 Adult Lung Transplants Kaplan-Meier Survival by Diagnosis (Transplants: January 1990 – June 2013) 100 Alpha-1 (N=2,904) CF (N=7,336) COPD (N=15,064) IPF (N=10,438) IPAH (N=1,584) Sarcoidosis (N=1,136)

80 Median survival (years): Alpha-1=6.5; CF=8.5; COPD=5.5; IPF=4.7; IPAH=5.7; Sarcoidosis=6.1 60

Survival (%) Survival 40

All pair-wise comparisons were significant at p < 0.05 except 20 Alpha-1 vs. IPAH, Alpha-1 vs. Sarcoidosis, COPD vs. IPAH, COPD vs. Sarcoidosis, IPAH vs. Sarcoidosis

0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Years 2015

JHLT.JHLT. 20152014 Oct;Oct; 34(10):33(10): 12641009--12771024 Adult Lung Transplants Functional Status of Surviving Recipients (Follow-ups: January 2009 – June 2014)

100% 10%

20% 80% 30%

40% 60% 50%

60% 40% 70%

80% 20% 90%

100% 0% 1 Year 2 Years 3 Years (N=8,010) (N=6,567) (N=5,446) 2015

JHLT.JHLT. 20152014 Oct;Oct; 34(10):33(10): 12641009--12771024 Adult Lung Transplants Employment Status of Surviving Recipients (Follow-ups: January 2009 – June 2014)

100%

80% Working (FT/PT Status unknown) Working Part Time 60% Working Full Time

40% Retired

Not Working

20%

0% 1 Year 3 Years 5 Years (N=5,408) (N=3,650) (N=2,535) 2015

JHLT.JHLT. 20152014 Oct;Oct; 34(10):33(10): 12641009--12771024 Adult Lung Transplants Rehospitalization Post Transplant of Surviving Recipients (Follow-ups: January 2009 – June 2014)

100%

80%

60%

40%

Hospitalized, Rejection + Infection Hospitalized, Infection Only 20% Hospitalized, Rejection Only Hospitalized, Not Rejection/Not Infection No Hospitalization

0% 1 Year 3 Years 5 Years (N=8,972) (N=6,021) (N=4,199) 2015

JHLT.JHLT. 20152014 Oct;Oct; 34(10):33(10): 12641009--12771024 Adult Lung Transplants Cumulative Morbidity Rates in Survivors within 1 and 5 Years Post Transplant (Follow-ups: April 1994 – June 2014)

Total Total Outcome Within number Within number 1 Year with known 5 Years with known response response Hypertension 51.7% (N=17,813) 80.7% (N=5,293)

Renal Dysfunction 22.5% (N=20,551) 53.3% (N=7,056) Abnormal Creatinine ≤ 2.5 mg/dl 15.7% 35.3% Creatinine > 2.5 mg/dl 5.0% 14.3% Chronic Dialysis 1.7% 3.0% Renal Transplant 0.1% 0.8% Hyperlipidemia 26.2% (N=18,510) 57.9% (N=5,643)

Diabetes 23.0% (N=20,502) 39.5% (N=6,941)

Bronchiolitis Obliterans Syndrome 9.3% (N=19,348) 41.1% (N=5,987)

2015

JHLT.JHLT. 20152014 Oct;Oct; 34(10):33(10): 12641009--12771024 Adult Lung Transplants Cumulative Post Transplant Malignancy Rates in Survivors(Follow-ups: April 1994 – June 2014)

1-Year 5-Year 10-Year Malignancy/Type Survivors Survivors Survivors No Malignancy 20,260 (96.3%) 6,191 (83.4%) 1,222 (70.9%)

Malignancy (all types combined) 780 (3.7%) 1,234 (16.6%) 501 (29.1%) Malignancy Skin 279 882 359 Type* Lymphoma 272 111 47 Other 200 294 139 Type Not Reported 29 10 2

Other malignancies reported include: adenocarcinoma (2; 2; 1), bladder (2; 1; 0), lung (2; 4; 0), breast (1; 5; 2); prostate (0; 5; 1), cervical (1; 1; 0); liver (1; 1; 1); and colon (1; 1; 0). Numbers in parentheses represent the number of reported cases within each time period.

* Recipients may have experienced more than one type of malignancy; therefore, the sum of individual malignancy types may be greater than the total number with malignancy. 2015

JHLT.JHLT. 20152014 Oct;Oct; 34(10):33(10): 12641009--12771024 Future Direction Lung transplant

Ex-vivo lung perfusion

Ambulatory ECMO

Induction of tolerance

Bioengineered lung tissue