Tens of thousands of patients with advanced lung diseases may be eligible to be considered as potential candidates for lung transplant around the world each year. The timing of referral, evaluation, determination of candidacy, and listing of candidates continues to pose challenges and even ethical dilemmas. To address these challenges, the International Society for Heart and Lung Transplantation appointed an international group of members to review the literature, to consider recent advances in the management of advanced lung diseases, and to update prior consensus documents on the selection of lung transplant candidates. The purpose of this updated consensus document is to assist providers throughout the world who are caring for patients with pulmonary disease to identify potential candidates for lung transplant, to optimize the timing of the referral of these patients to lung transplant centers, and to provide transplant centers with a framework for evaluating and selecting candidates. In addition to addressing general considerations and providing disease specific recommendations for referral and listing, this updated consensus document includes an ethical framework, a recognition of the variability in acceptance of risk between transplant centers, and establishes a system to account for how a combination of risk factors may be taken into consideration in candidate selection for lung transplantation. Tens of thousands of patients with advanced lung diseases may be eligible to be considered as potential candidates for lung transplant around the world each year. The timing of referral, evaluation, determination of candidacy, and listing of candidates continues to pose challenges and even ethical dilemmas. To address these challenges, the International Society for Heart and Lung Transplantation appointed an international group of members to review the literature, to consider recent advances in the management of advanced lung diseases, and to update prior consensus documents on the selection of lung transplant candidates. The purpose of this updated consensus document is to assist providers throughout the world who are caring for patients with pulmonary disease to identify potential candidates for lung transplant, to optimize the timing of the referral of these patients to lung transplant centers, and to provide transplant centers with a framework for evaluating and selecting candidates. In addition to addressing general considerations and providing disease specific recommendations for referral and listing, this updated consensus document includes an ethical framework, a recognition of the variability in acceptance of risk between transplant centers, and establishes a system to account for how a combination of risk factors may be taken into consideration in candidate selection for lung transplantation. Lung transplantation continues to grow as a field, with more than 4,500 transplants performed worldwide in 2019 at over 260 lung transplant centers.1Chambers DC Cherikh WS Harhay MO et al.The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult lung and heart–lung transplantation Report—2019; Focus theme: donor and recipient size match.J Heart Lung Transplant. 2019; 38: 1042-1055Google Scholar This trend reflects the expansion of acceptable donors and candidates made possible by clinical and scientific advances. Far fewer absolute contraindications for lung transplant candidacy exist now, compared to the time of publication of prior versions of this document, making the selection of candidates even more complex.2Orens JB Estenne M Arcasoy S et al.International guidelines for the selection of lung transplant candidates: 2006 update—a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation.J Heart Lung Transplant. 2006; 25: 745-755Google Scholar, 3Maurer JR Frost AE Estenne M Higenbottam T Glanville AR International guidelines for the selection of lung transplant candidates.Transplantation. 1998; 66: 951-956Google Scholar, 4Weill D Benden C Corris PA et al.A consensus document for the selection of lung transplant candidates: 2014–an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation.J Heart Lung Transplant. 2015 Jan; 34: 1-15Google Scholar This document is intended to express a consensus of the membership of the International Society for Heart and Lung Transplantation (ISHLT) to provide guidance for timely referral, assessment, optimization, and listing of potential lung transplant candidates. The current document updates the prior three, highlighting the recognition that comorbidities and other risk factors often interact to affect post-transplant survival benefit. While lung transplantation aims to improve both survival and quality of life, the expert consensus acknowledges that when making recommendations about allocating a scare resource, survival benefit is prioritized based on the ethical framework described in this document. This consensus document was developed in accordance with the ISHLT Standards and Guidelines committee document development policies. The consensus committee members were selected to represent the diversity of the society and were approved by the ISHLT Standards and Guidelines committee. Each member contributed to the literature searches, developed content, voted on the final consensus statements, and approved the final manuscript. Literature searches performed in early 2020 reviewed all pertinent articles, focusing on newer peer reviewed research available since publication of the 2014 consensus document.4Weill D Benden C Corris PA et al.A consensus document for the selection of lung transplant candidates: 2014–an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation.J Heart Lung Transplant. 2015 Jan; 34: 1-15Google Scholar During review of the document additional pertinent newly published articles were included, but a comprehensive review of literature was not repeated. Search terms, filters, and the resultant number of articles are available in the online supplement. The recommendations reflect expert synthesis of the current literature. In areas where there was paucity of evidence, the statements reflect consensus reached by the committee with an a priori threshold of >80% agreement on consensus statements. The worldwide scarcity of donor lungs requires rationing of this lifesaving but limited societal resource. This makes the selection of transplant candidates an ethical choice as well as a medical one. The fundamental ethical principles of “utility”, “justice”, and “respect for persons” (see Table 1) must, therefore, provide the framework for candidate selection and organ allocation systems.5Beauchamp T Childress J Principles of Biomedical Ethics.7th ed. Oxford University Press, New York2012Google Scholar,6Ethical Principles in the Allocation of Human Organs. Organ Procurement and Transplant Network. Accessed August 12, 2021. https://optn.transplant.hrsa.gov/resources/ethics/ethical-principles-in-the-allocation-of-human-organs/Google ScholarTable 1Ethical Principles for the Allocation of Donor Lungs6Ethical Principles in the Allocation of Human Organs. Organ Procurement and Transplant Network. Accessed August 12, 2021. https://optn.transplant.hrsa.gov/resources/ethics/ethical-principles-in-the-allocation-of-human-organs/Google ScholarPrincipleApplication to organ allocationUtilityTo maximize net benefit (e.g., using years of survival gained to prioritize allocation)JusticeTo distribute the benefits and burdens of organ allocation system in a fair way (e.g., using medical urgency to prioritize allocation, allowing special consideration for candidates for whom it is difficult to find a suitable organ)Respect for personsTo treat persons as autonomous with the right for self-determination (e.g., the right to give or withhold informed consent for a lung transplant) Open table in a new tab Since lung transplant is a lifesaving procedure, the principle of utility requires that survival be maximized when choosing transplant candidates. While some national allocation systems consider utility narrowly to determine survival only at a patient level, others may apply this principle more broadly on a societal level. Candidates should be carefully selected, as an unsuccessful lung transplant affects not only the individual who was transplanted, but also a potential alternative recipient who did not have the opportunity to be transplanted due to the prevailing organ shortage. Our recommendations have the explicit goal of maximizing long-term survival in order to provide net survival gains for society as a whole. As donor organs are obtained from society at large, equally important to utility is the principle of justice that requires all individuals with a potential survival benefit from lung transplant be given equal consideration and opportunity for transplant. Therefore, measuring an individual's “value” in society has no place in evaluation of transplant candidacy and this includes their contribution to society, social rank, or occupation. Similarly, group characteristics such as race, gender, or socioeconomic position should not be used to disadvantage access to transplant even if these subgroups are shown to have inferior transplant outcomes. Finally, the principle of respect for persons authorizes a candidate's right to self-determination or autonomy. To allow candidates the opportunity to exercise this right, transplant centers must provide transparent guidelines that explain the criteria for candidate selection and organ allocation. Referral for lung transplant is a complex process and, when possible, should begin before the need for transplant becomes urgent. Ideally, patients should be referred before they meet criteria for active waitlisting to provide an opportunity to introduce the concept of lung transplant, its requirements, and expected outcomes. Early referral may allow time for candidates to address modifiable barriers to transplant, such as obesity, malnutrition, medical comorbidities, or inadequate social support. Vaccination records should be reviewed and patients should receive vaccines as early as possible, as some vaccines require multiple injections over time, live vaccines are contraindicated after transplant, and any vaccine may be expected to have lower protective effect in the immunosuppressed. For patient referrals that are too early for full evaluation or with contraindications for transplant, specific parameters for the timing of re-referral and recommendations for ongoing optimization of candidacy should be provided. A full evaluation includes assessment of lung disease severity, anatomy, nutritional status, degree of frailty, presence and severity of comorbidities, psychosocial circumstances, and health-related behaviors that impact recovery and long-term survival. The timing of full evaluation for transplant should be informed by transplant providers’ assessment of the potentially modifiable risk factors for transplant, a patient's disease trajectory, and likelihood for prolonged wait for suitable donor organs (e.g., candidate with high level of HLA sensitization). Sometimes, a precipitous decline leads to referral under less than ideal circumstances. In these cases, every effort should be made to fully evaluate a potential candidate's eligibility in a similar manner to other candidates. Referral of patients on life sustaining interventions such as mechanical ventilation and / or extra-corporeal life support (ECLS) as a bridge to transplant (BTT), may be considered in highly selected patients at centers with expertise (see Table 2 and section on BTT below.)Table 2Risk factors for poor post-transplant outcomesRisk factors can change over time and may not be a contraindication for referral, but when present at the time of listing or while listed for lung transplantation may increase risk for poor transplant outcomes. There was 100% consensus (24 committee members) for the content of the entirety of Table 2.ABSOLUTE CONTRAINDICATIONS:•Candidates with these conditions are considered too high risk to achieve successful outcomes post lung transplantation.•Factor or condition that significantly increases the risk of an adverse outcome post-transplant and /or would make transplant most likely harmful for a recipient.•Most lung transplant programs should not transplant patients with these risk factors except under very exceptional or extenuating circumstances.1.Lack of patient willingness or acceptance of transplant2.Malignancy with high risk of recurrence or death related to cancer3.Glomerular filtration rate < 40 mL/min/1.73m2 unless being considered for multi-organ transplant4.Acute coronary syndrome or myocardial infarction within 30 days (excluding demand ischemia)5.Stroke within 30 days6.Liver cirrhosis with portal hypertension or synthetic dysfunction unless being considered for multi-organ transplant7.Acute liver failure8.Acute renal failure with rising creatinine or on dialysis and low likelihood of recovery9.Septic shock10.Active extrapulmonary or disseminated infection11.Active tuberculosis infection12.HIV infection with detectable viral load13.Limited functional status (e.g. non-ambulatory) with poor potential for post-transplant rehabilitation14.Progressive cognitive impairment15.Repeated episodes of non-adherence without evidence of improvement (Note: For pediatric patients this is not an absolute contraindication and ongoing assessment of non-adherence should occur as they progress through different developmental stages.)16.Active substance use or dependence including current tobacco use, vaping, marijuana smoking, or IV drug use17.Other severe uncontrolled medical condition expected to limit survival after transplantRISK FACTORS WITH HIGH OR SUBSTANTIALLY INCREASED RISK:•Candidates with these conditions may be considered in centers with expertise specific to the condition.•We may not have data to support transplanting patients with these risk factors or there is substantially increased risk based upon the currently available data, and further research is needed to better inform future recommendations.•When more than one of these risk factors are present, they are thought to be possibly multiplicative in terms of increasing risk of adverse outcomes.•Modifiable conditions should be optimized when possible.1.Age > 70 years2.Severe coronary artery disease that requires coronary artery bypass grafting at transplant3.Reduced left ventricular ejection fraction < 40%4.Significant cerebrovascular disease5.Severe esophageal dysmotility6.Untreatable hematologic disorders including bleeding diathesis, thrombophilia, or severe bone marrow dysfunction7.BMI > 35 kg/m28.BMI < 16 kg/m29.Limited functional status with potential for post-transplant rehabilitation10.Psychiatric, psychological or cognitive conditions with potential to interfere with medical adherence without sufficient support systems11.Unreliable support system or caregiving plan12.Lack of understanding of disease and / or transplant despite teaching13.Mycobacterium abscessus infection14.Lomentospora prolificans infection15.Burkholderia cenocepacia or gladioli infection16.Hepatitis B or C infection with detectable viral load and liver fibrosis17.Chest wall or spinal deformity expected to cause restriction after transplant18.Extracorporeal life support19.Retransplant <1 year following initial lung transplant20.Retransplant for restrictive CLAD21.Retransplant for AMR as etiology for CLADRISK FACTORS:•Risk factors with unfavorable implications for short and / or long-term outcomes after lung transplant.•While acceptable for lung transplant programs to consider patients with these risk factors, multiple risk factors together may increase risk for adverse post lung transplant outcomes.1.Age 65-70 years2.Glomerular filtration rate 40-60 mL/min/1.73m23.Mild to moderate coronary artery disease4.Severe coronary artery disease that can be revascularized via percutaneous coronary intervention prior to transplant5.Patients with prior coronary artery bypass grafting6.Reduced left ventricular ejection fraction 40-50%7.Peripheral vascular disease8.Connective tissue diseases (scleroderma, lupus, inflammatory myopathies)9.Severe gastroesophageal reflux disease10.Esophageal dysmotility11.Thrombocytopenia, leukopenia, or anemia with high likelihood of persistence after transplant12.Osteoporosis13.BMI 30-34.9 kg/m214.BMI 16-17 kg/m215.Frailty16.Hypoalbuminemia17.Diabetes that is poorly controlled18.Edible marijuana use19.Scedosporium apiospermum infection20.HIV infection with undetectable viral load21.Previous thoracic surgery22.Prior pleurodesis23.Mechanical ventilation24.Retransplant >1 year for obstructive CLADAbbreviations: AMR, antibody mediated rejection; BMI, body mass index; CLAD, chronic lung allograft dysfunction. Open table in a new tab Abbreviations: AMR, antibody mediated rejection; BMI, body mass index; CLAD, chronic lung allograft dysfunction. It is essential to account for medical comorbidities, psychosocial factors, and potential for rehabilitation in the evaluation of transplant candidates. Risk factors were identified that place potential candidates at increased risk for poor outcomes following lung transplant (Table 2). While it is important to consider the relative risk associated with a particular risk factor (e.g., increasing age or obesity), it is also relevant to think about the cumulative effect of multiple potential risk factors. Estimation of an individual's post-transplant survival based on published literature is challenging, highlighting the importance of future research to improve our ability to better predict outcomes. Further, the lung transplant community ought to consider an acceptable threshold for post-transplant survival to guide the complex task of allocation of this scarce resource in patients with high or substantially increased risk of poor post lung transplant outcomes. Age: Consideration of an upper age limit for lung transplant candidacy remains a controversial subject. In the 2006 and 2014 guidelines, age greater than 65 years in association with low physiologic reserve and/or other relative contraindications was considered a relative contraindication.2Orens JB Estenne M Arcasoy S et al.International guidelines for the selection of lung transplant candidates: 2006 update—a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation.J Heart Lung Transplant. 2006; 25: 745-755Google Scholar,4Weill D Benden C Corris PA et al.A consensus document for the selection of lung transplant candidates: 2014–an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation.J Heart Lung Transplant. 2015 Jan; 34: 1-15Google Scholar There has been no endorsement of an upper age limit as an absolute contraindication, but older individuals have worse long-term survival following lung transplant.7Lehr CJ Blackstone EH McCurry KR Thuita L Tsuang WM Valapour M Extremes of age decrease survival in adults after lung transplant.Chest. 2020; 157: 907-915Google Scholar The age of lung transplant recipients has increased over the past decade. In the United States (U.S.), candidates greater than 65 years of age now comprise more than 30% of the waiting list and are the age group with the highest transplant rate.8Valapour M Lehr CJ Skeans MA et al.OPTN/SRTR 2019 annual data report: lung.Am J Transplant. 2021; 21: 441-520Google Scholar With increasing experience in older recipients, several studies have shown that carefully selected older recipients may have the same short-term survival as younger recipients.9Hayanga AJ Aboagye JK Hayanga HE et al.Contemporary analysis of early outcomes after lung transplantation in the elderly using a national registry.J Heart Lung Transplant. 2015; 34: 182-188Google Scholar However, the results are skewed by selection bias, reflecting the fact that most recipients over the age of 65 years undergoing lung transplant are highly selected with very few comorbidities such as coronary artery disease and diabetes. Despite this selection bias and acceptable short-term outcomes, lung transplant recipients over the age of 70 years have decreased longer term survival.9Hayanga AJ Aboagye JK Hayanga HE et al.Contemporary analysis of early outcomes after lung transplantation in the elderly using a national registry.J Heart Lung Transplant. 2015; 34: 182-188Google Scholar As lung transplant centers become more comfortable with offering transplant for individuals in an older age demographic, it is important to remember the larger community has expressed preference to allocate this limited resource to younger patients first.10Tong A Howard K Jan S et al.Community preferences for the allocation of solid organs for transplantation: a systematic review.Transplantation. 2010; 89: 796-805Google Scholar Restricting access to transplant for older adults may be ethically justified both on the basis of justice and utility. The negative effect of advanced age on post-transplant survival is significant, especially for long-term survival, limiting the net utility of lung transplant in this population both at the individual and societal level. In addition, ethical paradigms related to just distribution of scarce resources, such as the “fair-innings” perspective, require that every individual has an equal chance to live a full life and that societal resources should be expended to maximize this chance. This may justify providing preferential access to younger candidates who have a stronger claim to an organ based on this account of justice. One option to address this issue is the consideration of allocation of lungs from older donors to older recipients, as this has been demonstrated to result in comparable outcomes.11Hall DJ Jeng EI Gregg JA et al.The impact of donor and recipient age: older lung transplant recipients do not require younger lungs.Ann Thorac Surg. 2019; 107: 868-876Google Scholar,12Katsnelson J Whitson BA Tumin D et al.Lung transplantation with lungs from older donors: an analysis of survival in elderly recipients.J Surg Res. 2017; 214: 109-116Google Scholar In summary, while older age is increasingly accepted in lung transplant candidates, the reduced long-term survival and the relevance of ensuring a just distribution of scarce resources should be considered. Malignancy: Age-appropriate and disease-specific cancer screening must be a part of every pre-transplant evaluation. Patients with a prior history of malignancy must undergo testing to confirm no evidence of residual or metastatic disease. Malignancy with high risk of recurrence or death is an absolute contraindication, but it is increasingly acknowledged in the context of lung transplant that not all neoplastic diseases are equal.13Al-Adra DP Hammel L Roberts J et al.Pre-transplant solid organ malignancy and organ transplant candidacy: a consensus expert opinion statement.Am J Transplant. 2021; 21: 460-474Google Scholar,14Al-Adra DP Hammel L Roberts J et al.Pre-existing melanoma and hematological malignancies, prognosis, and timing to solid organ transplantation: a consensus expert opinion statement.Am J Transplant. 2021; 21: 475-483Google Scholar Certain malignancies may not be significantly affected by immunosuppression and some may be managed post-transplant with aggressive surveillance and intervention (e.g., cervical dysplasia, anal dysplasia, and cutaneous non-melanoma skin cancer). Lung transplant may be an option in circumstances where the risk of recurrence is deemed to be very low based on the type and stage of cancer and with negative metastatic evaluation. Two recent consensus statements have addressed how to consider the distinct risks associated with pre-existing malignancies prior to transplant.13Al-Adra DP Hammel L Roberts J et al.Pre-transplant solid organ malignancy and organ transplant candidacy: a consensus expert opinion statement.Am J Transplant. 2021; 21: 460-474Google Scholar,14Al-Adra DP Hammel L Roberts J et al.Pre-existing melanoma and hematological malignancies, prognosis, and timing to solid organ transplantation: a consensus expert opinion statement.Am J Transplant. 2021; 21: 475-483Google Scholar Transplant centers should work closely with oncology specialists to evaluate each patient with a history of cancer to determine the stage-specific risk of recurrence or progression, which may be higher in the setting of immunosuppression, and to determine the necessary cancer-free period prior to listing.15Berastegui C LaPorta R López-Meseguer M et al.Epidemiology and risk factors for cancer after lung transplantation.in: Transplantation Proceedings. Elsevier, 2017: 2285-2291Google Scholar,16Acuna SA Huang JW Daly C Shah PS Kim SJ Baxter NN Outcomes of solid organ transplant recipients with preexisting malignancies in remission: a systematic review and meta-analysis.Transplantation. 2017; 101: 471-481Google Scholar Renal function: Increased risk has been demonstrated in lung transplant candidates with GFR <60 ml/min/1.73m2 by chronic kidney disease epidemiology equation (CKD-EPI) at the time of listing, especially in patients > 45 years of age.17Woll F Mohanka M Bollineni S et al.Characteristics and outcomes of lung transplant candidates with preexisting renal dysfunction.in: Transplantation proceedings. Elsevier, 2020: 302-308Google Scholar, 18Banga A Mohanka M Mullins J et al.Characteristics and outcomes among patients with need for early dialysis after lung transplantation surgery.Clin Transplant. 2017; 31: e13106Google Scholar, 19Degen DA Janardan J Barraclough KA et al.Predictive performance of different kidney function estimation equations in lung transplant patients.Clin Biochem. 2017; 50: 385-393Google Scholar, 20Osho AA Castleberry AW Snyder LD et al.The Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) equation best characterizes kidney function in patients being considered for lung transplantation.J Heart Lung Transplant. 2014; 33: 1248-1254Google Scholar, 21Osho AA Castleberry AW Snyder LD et al.Assessment of different threshold preoperative glomerular filtration rates as markers of outcomes in lung transplantation.Ann Thorac Surg. 2014; 98: 283-290Google Scholar Renal function is especially important following lung transplant as the peri-operative period is often complicated by hypotension and hypoperfusion of kidneys, and nephrotoxic calcineurin inhibitors remain the mainstay of maintenance immunosuppression. Outcomes are consistently worse for patients who develop renal failure requiring renal replacement therapy.18Banga A Mohanka M Mullins J et al.Characteristics and outcomes among patients with need for early dialysis after lung transplantation surgery.Clin Transplant. 2017; 31: e13106Google Scholar In select candidates with concomitant CKD, consideration may be given for possible simultaneous lung-kidney transplant or staged lung-kidney transplant (see multiorgan transplantation section below). Coronary Artery Disease (CAD): A high prevalence of CAD has been demonstrated in lung transplant candidates even in those without risk factors. Thus, evaluation for CAD should remain a part of transplant candidacy assessment.22Manoushagian S Meshkov A Evaluation of solid organ transplant candidates for coronary artery disease.Am J Transplant. 2014; 14: 2228-2234Google Scholar Consultation with a cardiologist familiar with lung transplant candidate selection should be considered for the development of protocols for pre-transplant assessment and management. Multiple retrospective studies over the past 5 years have shown that patients with mild to moderate CAD or those who have undergone revascularization for CAD may not have worse survival compared to patients without CAD.23Halloran K Hirji A Li D et al.Coronary artery disease and coronary artery bypass grafting at the time of lung transplantation do not impact overall survival.Transplantation. 2019; 103: 2190-2195Google Scholar, 24Khandhar SJ Althouse AD Mulukutla S et al.Post-operative outcomes and management strategies for coronary artery disease in patients in need of a lung transplantation.Clin Transplant. 2017; 31: e13026Google Scholar, 25Chaikriangkrai K Jyothula S Jhun HY et al.Impact of pre-operative coronary artery disease on cardiovascular events following lung transplantation.J Heart Lung Transplant. 2016; 35: 115-121Google Scholar, 26Koprivanac M Budev MM Yun JJ et al.How important is coronary artery disease when considering lung transplant candidates?.J Heart Lung Transplant. 2016; 35: 1453-1461Google Scholar It is important to point out that these patients have been highly selected and more often undergo single lung transplant.27Makey IA Sui JW Huynh C Das NA Thomas M Johnson S Lung transplant patients with coronary artery disease rarely die of cardiac causes.Clin Transplant. 2018; 32: e13354Google Scholar CAD was not associated with worse survival for patients undergoing percutaneous coronary intervention with stent placement prior to lung transplant or coronary artery bypass grafting (CABG) at the time of lung transplant.23Halloran K Hirji A Li D et al.Coronary artery disease and coronary artery bypass grafting at the time of lung transplantation do not impact overall survival.Transplantation. 2019; 103: 2190-2195Google Scholar In those patients with a history of prior CABG, bilateral lung transplant has been associated with inferior survival compared to those who undergo single lung transplant.28McKellar SH Bowen ME Baird BC Rama