LUNG TRANSPLANTATION: What the Internist Needs to Know
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1 LUNG TRANSPLANTATION: What the Internist Needs to Know Lorriana Leard, MD Assistant Clinical Professor Lung Transplantation Program Pulmonary and Critical Care Medicine UCSF Medical Center
2 Outline Introduction History of Lung Transplantation Evaluation of Candidacy and Listing Post Operative Care Complications
3 Introduction Lung transplantation has become accepted therapy for the treatment of carefully chosen patients with end stage lung disease who have not benefited from available therapies > 80% of patients survive the 1st year > 50% of patients survive beyond 5 years Majority of recipients return to productive activities Trulock EP et al. J Heart Lung Transplant 2004; 23:
4 ADULT LUNG TRANSPLANTATION Kaplan-Meier Survival by Era (Transplants: January 1988 June 2006) Survival (% : 1/2-life = 3.9 Years; Conditional 1/2-life = 6.9 Years : 1/2-life = 4.5 Years; Conditional 1/2-life = 7.2 Years /2006: 1/2-life = 5.5 Years; Conditional 1/2-life = 7.1 Years (N=4,390) (N=6,728) /2006 (N=11,537) Survival comparisons by era vs : p = : vs /06: p < vs /06: p < N at risk = 159 N at risk = 523 N at risk = Years ISHLT 2008 J Heart Lung Transplant 2008;27:
5 History of Lung Transplantation
6 History of Lung Transplantation Lung was the last of the major organs to be successfully transplanted 1963: 1 st Human lung transplant 58 year old prisoner with lung cancer Survived only 18 days 1980: 40 attempts, but only 9 survived >2 wks Hardy JD et al, JAMA 1963 Deron F et al, J Thorac Cardiovasc Surg 1971
7 History of Lung Transplantation Cyclosporine era-1981 First long-term survivors reported in 1982 by Stanford group 3 patients received combined Heart-lung transplant Single Lung Transplant by Cooper in Toronto, first patient survived 6.5 years Double sequential developed in c Reitz BA et al, NEJM 1982 Toronto Lung Transplant Group, NEJM 1986
8 Number of Transpla NUMBER OF LUNG TRANSPLANTS REPORTED BY YEAR AND PROCEDURE TYPE Bilateral/Double Lung Single Lung ISHLT 2008 J Heart Lung Transplant 2008;27: NOTE: This figure includes only the lung transplants that are reported to the ISHLT Transplant Registry. As such, this should not be construed as representing changes in the number of lung transplants performed worldwide.
9 AVERAGE CENTER VOLUME Lung Transplants: January 1, June 30, Number of cente Average number of lung transplants per year ISHLT 2008 J Heart Lung Transplant 2008;27:
10 Evaluation of Lung Transplantation Candidacy & Listing
11 Indications for Lung Transplantation Chronic end-stage lung disease Failed medical management For most patients the ultimate treatment rather than cure Trading one medical challenge for another Do not expect normal life expectancy in most patients J Heart Lung Transplant 2006; 25:
12 Indications for Lung Transplantation Pulmonary Vascular Disease Idiopathic pulmonary arterial hypertension Pulmonary hypertension secondary to systemic disease Eisenmenger s syndrome Obstructive Lung Disease COPD Alpha-1-anti-trypsin deficiency Suppurative Disease Cystic Fibrosis Bronchiectasis Restrictive Lung Disease Idiopathic pulmonary fibrosis Fibrosis secondary to connective tissue disorders Sarcoidosis Eosinophilic granuloma Lymphangioleiomyomatosis Occupational disease Hypersensitivity pneumonitis Bronchiolitis obliterans
13 ADULT LUNG TRANSPLANTATION Indications By Year (Number) CF IPF COPD Alpha-1 PPH Number of Transpla ISHLT 2008 J Heart Lung Transplant 2008;27: Transplant Year
14 Absolute Contraindications Malignancy Within 2 years [except basal & squamous skin cancer] 5+ years disease free for Breast >Stage 2, Colon > Dukes A, Melanoma >Level III, Renal cell extra-capsular Advanced organ dysfunction (kidney, liver, heart) Significant chest wall/spinal deformity Major psychosocial derangement Current tobacco or drug use Non-curable infections: HIV, Hepatitis B and C, Burkolderia cepacia J Heart Lung Transplant 2006; 25:
15 Relative Contraindications Age > 65 years Critical or unstable condition Severe limited functional status Colonization with highly resistant or virulent bacteria Severe obesity: BMI > 30 or < 18 Severe osteoporosis J Heart Lung Transplant 2006; 25:
16 AGE DISTRIBUTION OF LUNG TRANSPLANT RECIPIENTS (1/1985-6/2007) % of transplan Recipient Age ISHLT 2008 J Heart Lung Transplant 2008;27:
17 Case 1: Is the patient a candidate for Lung Transplantation? HPI 35 y/o male with CF Increased SOB x 2 weeks Copious greenyellow sputum Using nebs 3-4x/day Increased O2 requirements No fevers PMHx CF with Severe obstructive lung disease Hospitalized 2-3x per year for exacerbations Pancreatic insufficiency
18 Case 1: Is the patient a candidate for Lung Transplantation? Exam SaO2 84% on 5L, 94% on 50% FM Lung: diffuse early inspiratory crackles Labs HCO3 31 WBC , PCO 2 68, PO 2 49 FEV (23% pred), FVC 2.7 (50% pred)
19 Case 1 Is this patient a candidate for lung transplantation? A.No, it s too early B.No, it s too late C.Yes, he should be referred, but it may not be time to list him D.Yes, he should be listed ASAP E.Need more information
20 Refer Patients in the Transplant Window CLINICAL STATUS TOO EARLY TRANSPLANT WINDOW TOO LATE TIME 2 YEARS
21 Timing of Referral Referral suggested when: 1. Patients have < 50%, 2- to 3-year predicted survival AND /OR 2. NYHA class III or IV level of function
22 Timing of Referral Early referral is highly desirable as it allows for: Orderly process for assessment Management of areas of concern Patient education Optimizing management of underlying disease and any associated comorbidity, can lead to improved patient outcomes
23 Disease Specific Guidelines Cystic Fibrosis Referral Guidelines FEV 1 < 30% predicted FEV 1 > 30% with Increasing exacerbations ICU admission Rapid fall in FEV 1 Recurrent hemoptysis Transplant Guidelines PaCO 2 > 50 mmhg PaO 2 < 55 mmhg Pulmonary Hypertension Kerem et al. N Engl J Med 1992; 326: J Heart Lung Transplant 2006; 25:
24 Disease Specific Guidelines COPD Transplant Guidelines BODE index of 7-10 OR FEV 1 < 20% pred. & DLCO of < 20% pred. Hospitalizations and PCO 2 > 55 mmhg Pulmonary hypertension J Heart Lung Transplant 2006; 25: Glanville AR. Eur Respir J 2003; 22: Celli, BR. NEJM 2004;350:
25 Disease Specific Guidelines Pulmonary Fibrosis Referral Guidelines UIP Fibrotic NSIP Transplant Guidelines 10% drop in FVC over 6 months DLCO < 39% Desaturation with 6MWT J Heart Lung Transplant 2006; 25:
26 Disease Specific Guidelines Pulmonary Arterial Hypertension Referral Guidelines NYHA III or IV Rapidly progressive disease Transplant Guidelines Functional status: NYHA III or IV (despite therapy) Low exercise tolerance (< 350m in SMW) Syncope, hemoptysis or right heart failure CI < 2 L/min m2 RAP > 15 mmhg J Heart Lung Transplant 2006; 25:
27 How are patients listed? Lung Allocation Score (LAS) Score based on multiple clinical variables from patient Designed to reflect 1. Seriousness of patient's medical condition before transplant AND 2. Likelihood of success after a transplant Calculated with 1. Waitlist Urgency: predicts # of days individual is expected to live during the next year on the waiting list 2. Post-Transplant Survival: predicts # of days individual is expected to live during the 1 st year after lung transplantation
28 Lung Allocation Score
29
30 Lung Transplant Post Operative Care
31 Immunosuppression Therapy Maintenance Immunosuppression Therapy 1. Steroid: Prednisone 2. Calcineurin inhibitor: Tacrolimus (Prograf) 3. Antiproliferative agent: Mycophenolate mofetil (Cellcept) or Azathioprine (Imuran)
32 Prophylactic Therapy 1. Bacterial: Usually Vancomycin and Zosyn 2. CMV: Ganciclovir Valgancyclovir 3. PCP / Toxoplasma Septra 4. Aspergillus Voriconazole & inhaled amphotericin B
33 Post Lung Transplant Complications Pulmonary Nonpulmonary
34 Case 2: Post Lung Transplant Complication
35 Pulmonary Complications: Immediate Post-Op Primary graft dysfunction or ischemiareperfusion injury Anastomotic complications Infections Pleural space fluid collections Acute Rejection
36 Primary graft dysfunction
37 Primary graft dysfunction Major source of morbidity and mortality early after lung transplantation Occurs in as many as 10-20% of cases Presentation similar to adult respiratory distress syndrome or acute lung injury
38 Case 3: Post Lung Transplant Complication 59 y/o male s/p DLTx for IPF 1 month ago Increased SOB and low grade fever > 2 weeks Dry nonproductive cough
39 24 y/o female s/p DLTx for CF 2.5 yrs ago 2-3 weeks of increasing dyspnea, chest tightness & dry cough O2Sat 94-95% Low grade fever Case 4: Post Lung Transplant Complication
40 What is the diagnosis? A. Acute Rejection B. Cytomegalovirus infection C. Respiratory viral infection D. PCP E. Pulmonary edema
41 Acute Rejection More common in lung transplant than other solid organ transplants 60-75% have an episode in 1st year Vascular organ Lungs are exposed to environment Lung graft contains a large amount of antigen presenting cells and lymphocyte network
42 Acute Rejection Clinical signs non-specific CXR usually unremarkable FEV 1 drop occurs in both rejection and infection (sensitivity 60-75% in DLTx) Diagnosis made by TBBX (Sensitivity 80%) Transbronchial biopsies for surveillance remains a controversial topic, 66% of centers perform surveillance Hopkins PM. J Heart Lung Transplant 2002;21: Guilinger RA. Am J Resp Crit Care Med 1995;152:
43 Pulmonary Complications: Early Post Lung Transplant Acute Rejection Anastomotic complications Infections bacterial, fungal, viral, opportunistic Chronic Rejection: Bronchiolitis Obliterans Syndrome
44 Aspergillus Tracheobronchitis
45 Anastomotic complications
46 Case 5: Post Lung Transplant Complication 62 y/o female who is one year s/p DLT for Pulmonary Fibrosis 3 weeks of increasing LUQ discomfort SOB and cough Low grade fevers
47 Case 5: Post Lung Transplant Complication What is the diagnosis? A. Pneumococcal pneumonia B. MRSA Pneumonia C. Nocardia D. Aspergillus E. Rhizopus F. Cancer
48 Bronchoscopy revealed nodular polypoid lesions
49 Nocardia asteroides
50 CHRONIC REJECTION AFTER LUNG TRANSPLANT BRONCHIOLITIS OBLITERANS Broncholitis Obliterans (BO) 50-60% of recipients who survive 5 years Possibly universal Can begin early after transplant (median months) Accounts for >30% of deaths after 3rd year
51 100 FREEDOM FROM BRONCHIOLITIS OBLITERANS For Adult Lung Recipients (Follow-ups: April 1994-June 2005) Conditional on Survival to 14 days % Freedom from Years ISHLT 2006 J Heart Lung Transplant 2006;25:
52 CHRONIC REJECTION AFTER LUNG TRANSPLANT BRONCHIOLITIS OBLITERANS Probable Risk Factors Potential risk factors Acute Rejection Lymphocytic bronchitis CMV pneumonitis Anti-HLA pretransplantation CMV infection Community respiratory infection Donor antigen-specific reactivity Medical non-compliance GERD Older donor age + longer ischemic time Boehler A. Eur Respir J 2003; 22:
53 BRONCHIOLITIS OBLITERANS PROGRESSION OF SCAR What used to be the size of the dotted line has been scarred down to the central dark lumen
54 Obliterative Bronchiolitis
55 CHRONIC REJECTION AFTER LUNG TRANSPLANT BRONCHIOLITIS OBLITERANS BOS 0 BOS 0-p BOS 1 BOS 2 BOS 3 FEV 1 > 90% and FEF > 75% FEV % or FEF < 75% FEV % FEV % FEV 1 < 50%
56 Case 6: Post Lung Transplant Complication 64 year old man who underwent double lung transplantation for IPF. Post operative course complicated by aspiration Recovering, but then noted to develop a flattened affect Progressive decline in mental status Myoclonic jerking movements in arms Status epilepticus
57 Case 6: Post Lung Transplant Complication Head CT Scan Brain MRI (T2) Garg et. al. Postgrad Med J 2001
58 Case 6: Post Lung Transplant Complication What is the diagnosis? A. Intracranial bleed B. Reversible Posterior Leukoencephalopathy (RPLE) C. Toxoplasmosis D. Meningitis / encephalitis E. Post Transplant Lymphoproliferative Disorder (PTLD) Garg et. al. Postgrad Med J 2001
59 Reversible Posterior Leukoencephalopathy Clinical features Acute to subacute onset Neurological symptoms Headache Altered mental status / confusion / drowsiness Visual disturbances Seizures - usually generalized tonic-clonic Systemic signs Hypertension Metabolic derangements: Hypomagnesemia & Hypocholesterolemia
60 Case7: Post Lung Transplant Complication 67 y/o male with a lung transplant 3 years ago presents with complaints of rapidly progressive nodular lesions on scalp and forehead
61 2 weeks later Rapidly progressing nodular ulcerated lesions covering 60% of scalp
62 What is the diagnosis? A.Infection B.Drug Reaction C.Cancer
63 MALIGNANCY POST-LUNG TRANSPLANT FOR ADULTS Cumulative Prevalence in Survivors (Follow-ups: April June 2005) Malignancy/Type 1-Year Survivors 5-Year Survivors 7-Year Survivors No Malignancy 7968 (96.2%) 1756 (87.5%) 723 (81.3%) Malignancy (all types combined) 316 (3.8%) 252 (12.5%) 166 (18.7%) Malignancy Type* Skin Lymph Other Type Not Reported Other malignancies reported include: adenocarcinoma (2; 2; 2), bladder (2; 1; 0), lung (2; 4; 2), breast (1; 5; 4); prostate (0; 5; 3), cervical (1; 1; 1); liver (1; 1; 1). Numbers in parentheses represent the number of reported cases within each time period. * Recipients may have experienced more than one type of malignancy so sum of individual malignancy types may be greater than total number with malignancy. ISHLT 2006 J Heart Lung Transplant 2006;25:
64 Complications: Non-Pulmonary Neuro: AMS, Seizures (Reversible Posterior Leukoencephalopathy), tremor, neuropathy Malignancies: esp. Skin cancer, PTLD GI: Gastroparesis, GERD / aspiration, diarrhea, ileus, bowel perforation CV: Atrial tachyarrythmias, hypertension Renal: Renal insufficiency / failure, RTAs Endocrine: Diabetes, Hyperlipidemia Heme: Leukopenia / Anemia
65 POST-LUNG TRANSPLANT MORBIDITY FOR ADULTS Cumulative Prevalence in Survivors within 1 and 5 Years Post-Transplant (Follow-ups: April June 2007) Outcome Within 1 Year Total number with known response Within 5 Years Total number with known response Hypertension 52.10% (N = 9,982) 85.30% (N = 2,538) Renal Dysfunction 25.3% (N = 10,305) 37.0% (N = 2,798) Abnormal Creatinine < 2.5 mg/dl 17.20% 23.40% Creatinine > 2.5 mg/dl 6.40% 10.00% Chronic Dialysis 1.70% 3.10% Renal Transplant 0.00% 0.50% Hyperlipidemia 22.20% (N = 10,639) 53.60% (N = 2,829) Diabetes 25.70% (N = 10,269) 35.50% (N = 2,582) Bronchiolitis Obliterans 9.10% (N = 9,699) 33.70% (N = 2,128) ISHLT 2008 J Heart Lung Transplant 2008;27:
66 ADULT LUNG TRANSPLANT RECIPIENTS: Cause Of Death (Deaths: January June 2005) CAUSE OF DEATH 0-30 Days (N = 1,273) 31 Days - 1 Year (N = 1,886) >1 Year - 3 Years (N = 1,581) >3 Years - 5 Years (N = 910) >5 Years (N = 1,001) BRONCHIOLITIS 5 (0.4%) 87 (4.6%) 414 (26.2%) 263 (28.9%) 265 (26.5%) ACUTE REJECTION 65 (5.1%) 37 (2.0%) 26 (1.6%) 5 (0.5%) 7 (0.7%) LYMPHOMA 1 (0.1%) 51 (2.7%) 35 (2.2%) 14 (1.5%) 31 (3.1%) MALIGNANCY, OTHER 1 (0.1%) 50 (2.7%) 94 (5.9%) 73 (8.0%) 89 (8.9%) CMV 0 69 (3.7%) 21 (1.3%) 4 (0.4%) 3 (0.3%) INFECTION, NON-CMV 270 (21.2%) 685 (36.3%) 395 (25.0%) 172 (18.9%) 180 (18.0%) GRAFT FAILURE 361 (28.4%) 359 (19.0%) 278 (17.6%) 169 (18.6%) 170 (17.0%) CARDIOVASCULAR 131 (10.3%) 82 (4.3%) 53 (3.4%) 43 (4.7%) 52 (5.2%) TECHNICAL 107 (8.4%) 50 (2.7%) 11 (0.7%) 2 (0.2%) 3 (0.3%) OTHER 332 (26.1%) 416 (22.1%) 254 (16.1%) 165 (18.1%) 201 (20.1%) ISHLT 2006 J Heart Lung Transplant 2006;25:
67 100% ADULT LUNG RECIPIENTS Functional Status of Surviving Recipients (Follow-ups: April 1994 June 2007) 80% 60% 40% 20% No Activity Limitations Performs with Some Assistance Requires Total Assistance 0% 1 Year (N =6,863) 3 Year (N=4,355) 5 Year (N=2,503) 10 Years (N=419) ISHLT 2008 J Heart Lung Transplant 2008;27:
68 100% ADULT LUNG RECIPIENTS Employment Status of Surviving Recipients (Follow-ups: April 1994 June 2007) 80% 60% 40% 20% Working (FT/PT Status unknown) Working Part Time Working Full Time Retired Not Working 0% 1 Year (N=8,204) 3 Year (N=4,952) 5 Year (N=3,029) 10 year (N=635) ISHLT 2008 J Heart Lung Transplant 2008;27:
69 Key Points Lung Transplantation may be the final therapy option for advanced lung disease Patients must be carefully selected with factors varying by their underlying disease Early referral is an important for favorable outcomes Post lung transplant complications need to be recognized and treated aggressively Chronic rejection and infection remain major obstacles in long term survival Lung Transplant in correctly selected patients can improve duration and quality of life
70 Contact info: or
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