Lung Transplantation Indications

1. LungTransplantationIndications Esen KIYAN IstanbulUniversity IstanbulMedicalFaculty Department of RespiratoryDiseases

2. Selection of LTxCandidates Maurer JR, ERS / ATS / ISHLT 1998 Update: Orenset al, JHLT 2006 Limited randomized controlled trials Based primarly on expertopinions, patientcohorts, retrospective analysis of registers Mostrecommendationhave a moderatequality of evidence.

3. Goal of LTx Improvement in SURVIVAL and QUALITY of LIFE Itis better to refer too early than toolate(IPF, PAH)

4. General indicationsforLTx Clinically + functionally advanced lung disease Ineffective or unavailable medical therapy Limited life expectancy (<2-3 years) Orens JB, et al. International guideliines for the selection of lung transplant candidates: 2006 Update-A consensus report from the Pulmonary Scientific Council of the International Society for Heart Lung Transplantation. J Heart Lung Transplant 2006; 25: 745-755

5. Absolutecontraindications-I 1-Malignancy in the last 2 years (exceptnonmelanoma skin Ca) A disease free period of 3-5 yrsforpreviousneoplasms Indicationin BAC? 2-Untreatable another organ dysfunction (heart, liver, kidney) MultiorganTx? CAD not amenable to percutaneous intervention or bypass or CAD with severe LVF (HLTx ?)

6. Absolutecontraindications-II • 3-Noncurable chronic extrapulmonary infection (active HBV, HCV and HIV) • Histologicevidence of significantliverdamage • 4-Significant chest wall or spinal deformity, NMD • 5-Documented nonadherence with medical therapy • 6-Untreatable psychiatric condition • 7-No social support system • 8-Substance addiction(active or within the last 6 m)

7. Relativecontraindications •Age>65 years Poorerpostop. survival Olderpatients withgoodphysicalconditionand no comorbidity…..Tx •Criticalor unstable clinical condition(shock, MV or ECMO) •Severely limited functional status (poor rehabilitation potential) •Colonization with resistant bacteria, fungi or mycobacteria •Severe obesity (BMI>30 kg/m2) High postop mortality (Lederer DJ, Am J Respir Crit Care Med 2009) •Unstable extrapulmonary medical conditionssuch as CAD, DM HT, GER, peptic ulcer, symptomaticosteoporosis (TreatebeforeLT) •Prior pleurodesis(not a contraindicationin experiencedhands)

8. 2006 Age over 65 years Manageablecomorbidities HIV and hepatitis B/C Previous surgery including previous LT PostTxhighrecurrences in BAC De Perrot M, J Clin Oncol2004 Many centers exclude these patients Recent report showed no impact of BAC on 5-yr survival rate Ahmad U, Ann Thorac Surg 2012 Overall survival forBAC/cancer cohort (dashed line; n = 29) compared with general LTcohort (solid line; n = 21,524)

9. Recipient Age by Year of LT (1987 – 2011) Age cutoff 65 years (poor post-transplant survival in older) Trend to expand the age(usefunctional rather than chronologicalage) LT for adults ≥65 yrsrisenin USA from 7% in 2004 to 25% in 2010 Data taken from Organ Procurement and Transplantation Network ISHLT 2012

10. Age cutoff 65 years Recepients≥ 65 yrs vs youngercohorts ……1-yearand 3-year post-Txsurvivalratessimilar (Vadnerkar A, J HeartLungTransplant 2011, Kilic A. ThoracCardiovascSurg 2012) ISHLT registryreports : higherrisk of death (1 and 5yr) in olderrecipients (especially≥70yr) UNOS database: 10-yearsurvival rate amongrecepients≥ 65 yrs of 13% vs 23% forthose 50-64 yrsand 38% forthose<50 yrs Risk Factors For 1 Year Mortality with Recipient Age (LT 1998-2010) Vadnerkar A, J Heart Lung Transplant 2011 ISHLT 2012

11. Tx of patients on ECMO is controversial • ONOS database 1987-2008 • Total n=15,883; 51 on ECMO • Matched to 49 controls • Survival is worse with ECMO Mason DP, J Thorac Cardiovasc Surg 2010; 139: 765-73.

12. Ventilator dependent patients in ICU • UNOS database 1987-2008 • Total n=15,883; 586 mechanically ventilated • Matched to 566 controls • IncreasedpostTxmortality Mason 2010

13. OBESITY 2006 guideline: BMI>30 is a relative contraindication BUTunderweight recipients not mentioned 5978 recipients with CF, COPD and ILD followed for 4.2yrs: being underweight,overweight and obese associated with highpostTxmortality (LedererDJ, et al. A JRCCM 2009) adjusted for diagnosis, cardiopulmonary bypass, and transplant procedure type Impact of obesity and underweight on survivaltime after LT may be relatively small compared with the risk of death without Tx Obesity is an independent risk factor for primary graft dysfunction after lung transplantation (Lederer DJ, et al. AJRCCM 2011)

14. CF patientswithBurkholderiacepacia (BCC) Certain species of BCC causehighpostTxmortality (1-yearsurvival 67% with BCC compared with 92% without BCC. (ChaparoC, AJRCCM 2001) Majorityof centers exclude BCC Heterogenous collection of BCC species (genomovars) and excessive postTx mortality appears largely attributable to B cenocepacia (genomovar III) and to a lesser extent, B gladioli (Alexander BD, Am J Transplant 2008) Other BCC species have no adverse impact postTx survival and patients with these organisms should not be excluded from Tx (De Soyza A, J Heart Lung Transplant 2010; 29: 1395-1404).

15. Many centers are reluctant to transplant HCV-seropositive patients Fong TL, et al . Outcomes after lung transplantation and practices of lung transplant programs in the United States regarding hepatitis C seropositive recipients. Transplantation 2011; 91: 1293-6. 170 HCV(+) vs9259 HCV(-) recipients. 10/ 29programs(34.5%) exclude HCV(+)patients. Of19 programsaccepting HCV-(+) patients, only 5centers transplant actively viremic patients. Survivalrates similar (84.7% at 1 yr, 63.9% at 3 yrs for HCV+vs82.0% at 1 yr, 65.0% at 3 yrs for HCV-, P=0.712) Mostof these HCV (+) patients were probably nonviremic

16. Patients with HIV infection without AIDS and with sustained CD4 counts > 200/mm3 RahatHussain, MD; Harish Seethamraju, MD. Lung Transplantation in Human Immunodeficiency Virus (HIV): Chest. 2011 A 65-year-old male with HIV and IPF with secondary PH (on presentation had a CD4 count of 450/uL and a non-detectable HIV viral load on HAART) Re-started on his previous HAART therapy 5 days after the transplant. Dischargedhome 17 days after his surgery. Currently, 12 months post-transplant, his CD4 count is 540/uL, and HIV viral load remains non-detectable. .

17. ReferralforTxassessment • 2-3 yearpredictedsurvival <%50 • NYHA classIII or IV (beingambulatory is ideal) • 6DYT • Chance of survivingwaiting time depends on: Waiting time (bloodgroup, height) Underlyingdisease (IPAH, CF, IPF vs empysema, Eisenmenger) Allocation system Decisiontorefershould be based on clinical+ laboratory+ functionalfindings

18. ReferralandListingIndicationsfor COPD, ILD, CF, and PAH AdultLTxMajor Indications By Year (%) ISHLT 2012 J Heart Lung Transplant.  2012 Oct; 31(10): 1045-1095

19. Indications forLTx inCOPD BODE index of 7–10 or at least one of the following: Hospitalization for acutehypercapnicexacerbation(PaCO2>50 mmHg) Pulmonary hypertension ±corpulmonaledespite LTOT FEV1 <20% and either DLCO <20% or homogeneous distribution of emphysema BODE score: grading systemto predict outcome in COPD Celli et al, N Engl J Med 2004

20. LVRS / EB valveLTx LTx Up to 60-65 years FEV1 < 30% DLCO < 20% PAH Hypercapnia Life expectancy <2 years LVRS Up to 75-80 years > 20% FEV1 < 35% DLCO > 20% No PAH No hypercapnia Life expectancy > 2 years

21. Pulmonaryfibrosis Poor prognosisand no effective therapy Prognosisredictedeasily in UIP but not in NSIP Patients usually come too late High mortality on waiting list (latereferral) Secondary cancers? Kim et al. Proc Am Thorac Soc 2006;3:285-92

22. Indications for LTxreferral: IPF and NSIP Histologicorradiographicevidence of UIP (irrespective of VC) Histologicevidence of fibrotic NSIP Referringat time of diagnosis is better

23. Txindications for IPF andNSIP • Histologic or radiographic evidence of IPF and any of the following: • DLCO <39% predicted • At least10% decrement in FVC during 6 months of follow-up • Decrease in pulse oximetrybelow88% during 6-MWT • Honeycombing on HRCT (fibrosisscore>2) • Histologic evidence of NSIP and any of the following: • DLCO <35% • ≥10% decrease in FVC or 15% decrease in DLCO during 6 m of follow-up

24. Guidelinesfor LTX : CF Referralindications • FEV1 < 30% or a rapid decline in FEV1 • Exacerbation requiring ICU stay • High frequency of exacerbations requiring antibiotic • Refractory and/orrecurrent hemoptysis or pneumothorax • LTxindications • Oxygen-dependent respiratory failure • Hypercapnia • Pulmonary hypertension

25. Indications for LTX referral: pulmonary arterial hypertension Therapyfails in 25% and prognosis is poor in WHO-FC III or IV Disease-specifictherapy .....reduced patientreferral Prognosis varies according to the aetiology PAH with CHD: better survival PAH with CTD: worse prognosis than IPAH PVOD and capillary haemangiomatosis: worst prognosis (list at diagnosis )

26. Pulmonaryarterialhypertension ISHLT guidelines for transplantation referral -NYHA class III or IV, irrespective of ongoing therapy -Rapidly progressivedisease ISHLT guidelines for listing/transplantation -NYHA class III or IV on maximal medical therapy -Low (<350m) or declining 6MWD -Failing therapy with iv epoprostenol or equivalent -Cardiac index<2L/min/m2 -RA pressure>15mmHg