Managing Long-Term Issues – Post Lung Transplant

Lung Transplantation 

“In it for the Long Haul: 

Long-Term Management” 




Jeff Golden, MD 

Professor of Medicine and Surgery 

University of California, San Francisco 

Medical Director, Lung Transplantation 

Director of Clinical Research, 

Interstitial Lung Disease Program 

Email: jeffrey.golden@ucsf.edu 

ILD: SALLY MCLAUGHLIN 415 353-2577 

LUNG TRANSPLANTATION: 

KERRY KUMAR 415 353-9338 

What’s New, What Matters, 

What’s Next 

UCSF TRANSLANT 2010 

# of patients 

45 

40 

35 

30 

25 

20 

15 

10 

5 

Number of Lung Transplants Per 

Year at UCSF 

31 

32 

28 

29 

15 

13 

11 

12 

10 10 10 

8 

6 

6 

4 

1 

35 

41 

Heart and Lung Transplant 

Quality Indicator 

Patient Survival 

UCSF Heart 

Transplant 

Observed 

UCSF Heart 


Expected 

UCSF Lung 


Observed 

UCSF Lung 


Expected 

1 Month 96.52% 94.97% 97.56% 95.85% 

1 Year 85.81% 81.14% 89.28% 83.18% 

3 Years 69.91% 60.44% 74.36%* 63.02% 

0 

1991 

1992 

1993 

1994 

1995 

1996 

1997 

1998 

1999 

2000 

2001 

2002 

2003 

2004 

2005 

2006 

2007 

2008 

SRTR- Scientific Registry Transplant Recipients 

•For Patients Receiving their First Transplant of this type between 

07/01/2006 and 12/31/2008 for the 1 Month and 1 Year Cohorts; between 

01/01/2004 and 06/30/2006 for the 3 Year Cohort 

• * Statistically Significant Updated 01/05/2010 

1







•50% Five Year Survival 

–15 - 20 years without improvement in five year survival 

–Risks to Improvement of Long Term Survival 

RISK TO LONG TERM OUTCOME 

Immunosuppression rather than understanding of mechanisms 

Bronchiolitis Obliterans - Chronic Rejection 

Challenges of newer categories of recipients 




BRONCHIOLITIS OBLITERANS 

PROGRESSION OF SCAR 

Outline 

•Bronchiolitis Obliterans Syndrome (BOS) 

-Mortality & Morbidity 

- Mechanism - Immune and non-immune 

- Interventions 

–Complications Post-transplantation 

-Immunosuppression and morbidity 

i.e. Infection, cancer 

•New categories of recipients 

future management challenges 

What used to be the size of 

the dotted line has been 

scarred down to the central 

dark lumen 

2

Causes of Death Following 


>3 years post transplant 

*Bronchiolitis Obliterans-80% of deaths 

Graft failure 

and/or 

Infection 

Bronchiolitis Obliterans 

Chronic Rejection 

“BOS” - Bonchiolitis Obliterans Syndrome 

FEV 1 

– BOS Major Barrier to Long Term 

Success 

*BRONCHIOLITIS OBLITERANS SYNDROME 

“BOS” 

FEV 1 DECREASES >20% 

– Mechanism of BOS: Work in Progress 

• Immune Mechanism 

– Acute Vascular Rejection 

ACUTE VASCULAR REJECTION 

Transbronchial Biopsy (TBBx) 



“BOS” - Bonchiolitis Obliterans Syndrome 

FEV 1 

– BOS Major Barrier to Long Term Success 

– Mechanism of BOS: Work in Progress 

• Immune Mechanism 

– Acute Vascular Rejection 

– Acute Airway Rejection 

» Lymphoycitic bronchitis/bronchiolitis 

3

Acute Airway Rejection 

Inhaled Cyclosporine 

Separate Interventions for Separate Processes 

Lymphocytic 

Bronchitis/Bronchiolitis(LBB): 

A Risk Factor for BO 

Youseem, 1993, Ross 1997, Hussain, 1999, 

Hays 2008 ATS 

Cyclosporine by inhalation 

Epithelial administration to 

avert airway rejection & 

ongoing injury, inflammation 

and fibrosis ending in 

bronchiolitis obliterans 

Systemic cyclosporine 

Systemic administration to 

avert vascular rejection, 

halting lymphocytic 

recruitment and activation 

Chronic rejection-free survival probability 

Inhaled Cyclosporine 

Kaplan-Meier Plot of Chronic 

Rejection-Free Survival 

1.0 

0.9 

0.8 

0.7 

0.6 

0.5 

0.4 

0.3 

0.2 

0.1 

0.0 

CyIS 

Placebo 

Relative risk = 0.279 

P = .001 

3.6-fold increase in median chronic 

rejection-free survival duration 

0 6 12 18 24 30 36 42 48 54 60 

N at risk 

Time, months 

Placebo 30 24 19 14 12 6 5 4 3 1 0 

CyIS 26 26 24 21 16 12 11 9 5 0 0 

Azithromycin: Prevention of BOS 

Randomized placebo-controlled trial to prevent 

BOS after lung transplantation 

2 year study, 83 patients 

Vos R. 2010 

Azithromycin reduced BOS v placebo 

12.5% vs 44.2% p= 0.0017 

4

Rejection: 

Newer Categories of Acute Lung Rejection 

Immune Mechanism of Bonchiolitis Obliterans Syndrome: 

• Acute Vascular Rejection 

• Lymphcytic bronchitis/bronchiolitis - Airway Rejection 

– Inhale Immunosuppression 

– azithromycin 

• Antibody Mediated Rejection-Donor Specific Antibody 

Humoral Mediated Rejection 

• Role in Lung Transplantation? 

• How diagnose ? 

Donor Specific Antibodies (DSA) 

Measurement Technique (s) 

Pathology - C4D 

• Treatment? 

–Plasmapheresis, Rituxamab, IVIG 

Donor SpecificAntibody to Single HLA Antigen 



* 







* PE - Phycoerthythrin 

5









Donor Specific anti-HLA Antibodies 

and Antibody-Directed Therapy after 


RR Hachem, MR Morrell, RD Yusen, AA 

Aloush, M Liu, BF Meyers, GA Patterson, 

T Mohanakumar, EP Trulock 

DSA clearance and survival 

DSA & BOS 

summary 

• DSA surprisingly 

common 

• Role of treatment? 

• DSA clearance 

favorable outcome 

Sensitization 

*PGD 

DSA 

BOS 

• NEED: Randomized 

Controlled Trial 

HLA mismatch 

*Primary Graft Dysfunction 

6

Chiron Briefing Document Figure 2.2-2 


Syndrome (BOS) 

Immune Mechanisms 

• Acute Vascular Rejection 

• Acute Airway Rejection 

– Lymphocytic bronchitis/bronchiolitis 

• Antibody Mediated Rejection-Donor Specific Antibody 

The Path to Chronic Rejection 

Immune dependent factors 

• Acute rejection 

• Lymphocytic 

bronchitis/bronchiolitis 

• Humoral Mediated 

Rejection- 

– DSA- (donor specific 

antibody) 

Small airway epithelial injury 

Excessive fibroproliferation 

Aberrant tissue repair 

Immune independent factors 

• Primary Graft Dysfunction 

• GERD/microaspiration 

• CMV pneumonitis 

• Community Viral 

Bronchiolitis obliterans (OB) 

Gastroesophageal Reflux Disease 

Early Fundoplication Prevents Chronic Allograft 

Dysfunction in Patients with GERD 

Cantu 2004 Ann Thorac Surg 

•Post-Transplantation 

14 Lung Transplant Recipients with GERD 

“immediate” fundoplication 

BOS free up to three years 

"…we suggest that GER should be considered as a 

potentially reversible cause of BOS among lung transplant 

recipients." 

7

Effect of GERD on Survival 

Lung Transplantation: 

Bronchiolitis Obliterans Syndrome (BOS) 

& 

Gastroesophageal Reflux Disease 

•Increased GERD in Pre-Transplant Populations 

IPF, Cystic Fibrosis 

•GERD worse Post-Transplantation 

•Esophageal Wrap Avoids BOS ? 

Davis RD Jr, et al. Improved lung allograft function after fundoplication in patients with 

gastroesophageal reflux disease undergoing lung transplantation. J Thorac Cardiovasc 

Surg. 2003 Mar;125(3):533-42. 

•Azithromycin reduces GE Reflux and aspiration 

»Mertins V 

–24 hour Impedance-pH 

–BAL bile acid level 

Chiron Briefing Document Figure 2.2-2 

The Path to Chronic Rejection 

Immune dependent factors 

• Acute rejection 

• Lymphocytic 

bronchitis/bronchiolitis 

• Humoral Mediated 

Rejection- 

– DSA- (donor specific 

antibody) 

Small airway epithelial injury 

Excessive fibroproliferation 

Aberrant tissue repair 

Immune independent factors 

• Primary Graft Dysfunction 

• GERD/microaspiration 

• CMV pneumonitis 

• Community Viral Infections 

Respiratory Syncytial Virus (RSV) 

in 75 year old Lung Transplant Recipient 

Bronchiolitis obliterans (OB) 

8

Viral Syndrome Post-Transpant 


Community Acquired Respiratory Viruses 

• Novel Techniques of Detection 

• Pathogenesis - Bronchiolitis Obliterans Syndrome (BOS) 

• Clinical Management 

Eosinophils 

Bronchoscopy #2 

Clinical Presentation* 

Vessel 

• DFA neg 

• Viral PCR: metapneumovirus and rhinovirus 

• AFB and Fungal NGTD 

• Transbronchial Lung Biopsy: Rejection 

• Vascular Rejection A3* 

• 

_____________________________ 

* Severity Scale A1 - A4 

9

Is community-acquired respiratory virus 

infection associated with Bronchiolitis 

Obliterans Syndroms 

• Gottlieb J 2009, 

Prospective Investigations 

of Community Acquired Virus in 

lung transplant recipients 

Community Acquired Respiratory Viruses (CARV) 

and Risk of BOS 

• Single center prospective cohort study, Hannover, 

Germany, Nov 2005- April 2006 

• 388 post lung transplant pts screened 

– viral sxs 

– URTI sxs: Nasopharyngeal swab for DFA, no PCR 

– LRTI sxs: Swab + BAL for DFA and PCR 

• 7.7% of patients enrolled had CARV 

– Parainfluenza, RSV, metapneumovirus, coronavirus, 

rhinovirus, influenza 

Gottlieb, Transplantation 2009 

Kumar 2010 

Community Acquired Respiratory Viruses & 

Risk of Bronchiolitis Obliterans Syndrome 

Community Viruses Risk of BOS 

1year incidence of BOS 

25% in virus + pts 

9% in virus – pts 

P = 0.01 

Gottlieb, Transplantation 2009 

Community Acquired 

Respiratory Viruses 

and Lung Transplantation 

• Pathogenesis-Bronchiolitis Obliterans Syndrome (BOS) 

• Clinical Management Implications 

– Prevent Exposure 

– Call transplant center with “cold” symptoms 

– Vaccination -Danziger L, Transplantation 2010 

10


Challenge: Understanding Mechanism 




Non- 

alloimmune 

factors: • Infection 

• GERD 

• Others 

Increase 

systemic 

immune 

suppression 

Immune 

activation 

Bronchiolitis 

obliterans 

Outline 










Increased Potential for 

Infection 

Aspergillosis in Lung 

Transplantation 

• Immunosuppression 

• Donor lung infection 

• Acute epithelial injury 

• Ischemia 

• Rejection 

• Mucociliary clearance 

• No cough reflex 

• No Lymphatic defense 

• Airway function 

• Anastomosis 

• Obliterative bronchiolitis 

A Major Problem 

• Incidence (colonization or disease) 8 - 46% 

• Invasive Aspergillus mortality rate > 60% 

• Up to 13% of all post-lung transplant deaths 

Cahill. 1997 112(5):1160 

Nunley Chest. 2002 122(4):1185 

Westney. Transplantation. 1996 61(6):915 

11

Aspergillosis in Lung 

Transplantation 

Management of Long Term Complications 

Voriconazole: Prophylaxis and Tx 

? Risk of skin cancer and Voriconazole 

Voriconazole and geographic location are 

independent risk factors for Squamous cell 

carcinoma 

SKIN CANCER INCIDENCE 

Kidney, Heart Transplant 

Years post Transplant: 

10 years 10-30% 

20 years 40-60% 

Lung Transplant 

7 years 12% 

Vadnerkar 2010 

Nguyen MH 2010 




Outline 










Lung Transplantation & long term 

management: 

New recipient categories create future 

challenges 

•Lung Allocation Score: recipient risk 

»Russo MJ 

•Lung Fibrosis: DVT/emboli 

•Age 

•Coronary Artery Disease 

•Novel Patient Categories 

Bronchoalveolar cell carcinoma (BAC) 

Scleroderma 

Saggar R, UCLA 

12

Lung Allocation Score (LAS) 

Emergent Lung Transplantation 

In Fibrotic Lung Disease 

• New transplant guidelines are based on a lung 

allocation score (LAS) 

• How sick is the patient? 

• LAS (0 - 100) prioritizes lung allocation 

• IPF & Cystic Fibrosis favored over Emphysema 

•Lung Allocation Score: Emergent Organ Availability: 

•ECMO extracorporeal membrane oxygenation 

RE-TRANSPLANTATION 

Yusen RD 2010 

Post LAS 5% of lung transplants 

May 2005 

Median waiting time 

Pre LAS 146 Days 

Post LAS 45 Days 

1-year survival 

Re-Transplantation 70% 

Primary Transplant 83% 

Lung Transplantation & long term 

management: 

New recipient categories create future 

challenges 

•Lung Allocation Score: recipient risk 

•Lung Fibrosis: DVT/emboli 

•Age 

•Coronary Artery Disease 

•Novel Patient Categories 

Bronchoalveolar cell carcinoma (BAC) 

Scleroderma 

Saggar R, UCLA 

13




Outline 










Lung Transplantation & long 

term management: 

future challenges 

•quality of life 

• 

–Assess more than survival 

–unique10 year survivors 

•Rutherford 2005 

–UCSF Jon Singer 




•50% Survival by 5 years post-transplant 

•Bronchiolitis Obliterans barrier to success 


•Lung transplant is a frontier 

•The standard of care is dynamic 

14

Managing Long-Term Issues – Post Lung Transplant

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