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.
Keywords
Lung transplantation continues to grow as a field, with more than 4,500 transplants performed worldwide in 2019 at over 260 lung transplant centers.
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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.- Chambers 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: 1042-1055
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Goal of this consensus document
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.
Methods
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.
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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.General ethical framework and allocation systems
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.
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Ethical 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/
Table 1Ethical Principles for the Allocation of Donor Lungs
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Ethical 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/
| Principle | Application to organ allocation |
|---|---|
| Utility | To maximize net benefit (e.g., using years of survival gained to prioritize allocation) |
| Justice | To 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 persons | To treat persons as autonomous with the right for self-determination (e.g., the right to give or withhold informed consent for a lung transplant) |
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.
Timing of referral, evaluation, and listing
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 outcomes
| Risk 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:
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RISK FACTORS WITH HIGH OR SUBSTANTIALLY INCREASED RISK:
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RISK FACTORS:
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Abbreviations: AMR, antibody mediated rejection; BMI, body mass index; CLAD, chronic lung allograft dysfunction.
Risk factors to be considered
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.
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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.7
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.8
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.9
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.9
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.
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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.11
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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.
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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.13
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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.15
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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.
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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.18
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.
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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.23
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It is important to point out that these patients have been highly selected and more often undergo single lung transplant.27
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.23
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.28
Considering the results of these studies, CAD should not be considered an absolute contraindication. However, CAD has been recognized as a potential marker for systemic atherosclerotic disease and patients with CAD should have additional evaluation for other underlying vascular diseases, including cerebrovascular and peripheral vascular disease.25
Peripheral Vascular Disease (PVD): PVD is considered a risk factor for limiting rehabilitation post-transplant and poses a risk of ischemic limb complications with peri-operative use of ECLS. PVD frequently coexists with CAD and cerebrovascular disease and may be a marker of overall medical comorbidity in a potential candidate. Although a specific threshold for PVD cannot be determined, it may be important in the evaluation of a candidate's suitability for transplant.
Heart Failure: Although patients with right heart failure can successfully undergo lung transplant, there are few data about patients with left ventricular dysfunction because the majority of centers will not transplant patients with a low left ventricular ejection fraction.
Connective Tissue Disease (CTD): Multiple studies have demonstrated that carefully selected patients with CTD have no difference in survival or allograft dysfunction compared to patients undergoing lung transplant for other indications.
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Screening for extra-pulmonary systemic disease in collaboration with a multidisciplinary team, including rheumatologists, gastroenterologists, and nephrologists, is essential in these candidates as cardiovascular (including conduction abnormalities, myocarditis, heart failure, and CAD), gastrointestinal, renal, musculoskeletal, or other organ system involvement may affect post-transplant outcomes and need to be considered on a case-by-case basis. Patients with inflammatory myopathies should undergo comprehensive screening for occult neoplasm.31
Esophageal Dysfunction / Gastrointestinal Dysmotility/ Gastroesophageal reflux (GER): Post-transplant GER is variably associated with increased risk of acute rejection, pulmonary infection and earlier development of chronic lung allograft dysfunction (CLAD).
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Anti-reflux surgery pre-transplant and early post-transplant has been associated with a decrease in the development of early allograft dysfunction.34
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It is important to note that conventional anti-reflux surgery may not be a suitable option in many cases due to concurrent esophageal dysmotility and/or gastroparesis. Diseases characterized by GER and esophageal dysfunction, such as scleroderma or other connective tissue disorders, may pose specific challenges for a transplant recipient due to increased risk of micro- or macro-aspiration. Despite these risks, studies of scleroderma recipients, undergoing lung transplant at centers with expertise with this patient population, have demonstrated that esophageal dysfunction does not appear to impact outcomes.36
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Hematologic abnormalities: Thrombocytopenia, leukopenia, or anemia may contribute to peri-operative complications and may limit use of optimal maintenance immunosuppression and necessary antimicrobial prophylaxis following lung transplant. Untreatable hematologic disorders including bleeding diathesis, thrombophilia, or severe bone marrow dysfunction can substantially increase the risk of poor post-transplant outcomes and lung transplant should be considered only in highly selected cases. Patients with telomeropathy should undergo detailed evaluation, potentially including bone marrow biopsy, due to their concurrent risk of hematologic abnormalities including myelodysplastic syndrome.
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Body Mass Index (BMI): The preponderance of current evidence supports an increased risk of primary graft dysfunction and post-transplant mortality for obese recipients compared with normal or overweight candidates.
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In one study, when stratified by degree of obesity, the risk of mortality was increased for patients with a BMI >35 and not in those with BMI 30-34.9.42
These patients should be encouraged to lose weight as the magnitude of pre-transplant weight loss is directly correlated with improvements in post-transplant survival for candidates who are not underweight.43
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While low BMI has been associated with increased mortality, Cystic fibrosis (CF) recipients with BMI <17 kg/m2 have a survival rate similar to other commonly transplanted patients.45
Of note, the mechanisms underlying adverse effects of high or low BMI on transplant outcomes are not well understood. Recent data show that BMI is not an accurate surrogate of body composition with ongoing research efforts to better assess and risk stratify transplant candidates.Hypoalbuminemia: Hypoalbuminemia (<3.5 g/dl) has been independently associated with decreased survival and post-operative complications.
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It is also a predictor of poor survival for lung transplant candidates while on the waiting list including those who require ECLS prior to lung transplant.49
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Functional Status and Frailty: Frailty, defined as a generalized vulnerability to stressors resulting from the presence of multiple physiologic deficits, is associated with an increased risk of waitlist and post-transplant mortality.
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However, frailty in lung transplant candidates is often attributable to advanced lung disease and may improve following transplant.54
When considering frailty in lung transplant candidates, it should be noted that optimal assessment tools for frailty are not yet accepted and caution is warranted in using frailty for listing decisions. Functional status remains an important predictor of post-transplant outcomes.55
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Pre- and post-transplant pulmonary rehabilitation should be recommended for transplant candidates and recipients.57
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Human Leucocyte Antigen (HLA) Antibodies: Elevated HLA specific antibodies detected in peripheral blood may make finding a compatible donor difficult and may predict poor outcomes.
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However, some centers describe successful lung transplantation despite positive cross match.62
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Cut-off levels for organ acceptance and the optimal methods for detection of functional donor specific antibodies have not been determined. In addition, there is significant variability among transplant centers with regards to pre-transplant desensitization in highly sensitized candidates with insufficient evidence of effect.Infectious disease risk factors
Multi-drug resistant organisms
Advances in diagnostic techniques, new active drugs, and efficiency in both drug and disease monitoring have improved lung transplant results in individuals colonized or infected with multi-drug resistant organisms. While these organisms are no longer universally considered an absolute contraindication, several pose substantial risk. These should be managed by centers with specialized experience and guidance by an infectious disease consultant experienced in the field of lung transplantation.
Non-tuberculous mycobacteria (NTM): M. abscessus subspecies abscessus is considered a high risk factor for lung transplant due to the intrinsic resistance to antimicrobials, tendency to relapse even after prolonged therapy, and association with CLAD after transplant.
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Increasing evidence shows that intensive treatment and surveillance pre and post-lung transplant may lead to better results.66
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Thus, patients with M. abscessus should be managed at centers with expertise and protocols for managing this infection.Non-aspergillus molds: Scedosporium apiospermum or Lomentospora prolificans may lead to severe disseminated infections after lung transplant. For S. apiospermum, acceptable results have been observed, while L. prolificans still seems to incur a substantially higher risk due to its resistance patterns. Decisions about candidacy must be individualized, considering the susceptibilities, efficacy of synergistic antifungal therapy, and potential reservoirs of infection.
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- Parize P
- Boussaud V
- Poinsignon V
- et al.
Clinical outcome of cystic fibrosis patients colonized by Scedosporium species following lung transplantation: A single-center 15-year experience.
Transpl Infect Dis. 2017; 19 (Epub 2017 Aug 1. PMID: 28618155)https://doi.org/10.1111/tid.12738
Burkholderia cepacia complex: Burkholderia cepacia complex includes several genotypically distinct bacteria, the most common of which are B. cenocepacia and B.multivorans. Of these, particularly B. cenocepacia has been associated with post-transplant infections and increased mortality especially within the first 6-12 months.
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While it may be considered an absolute contraindication at many centers, patients may be candidates at specialized centers that have attained satisfactory outcomes with protocols implementing newer antibiotic combinations and intense management of sinusitis.74
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Viral pathogens
Hepatitis B virus (HBV): Antivirals for HBV infection are available and safe to use post-transplant for prophylaxis and treatment. Consequently, HBV in patients without liver disease is not a barrier to lung transplant.
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Hepatitis C virus (HCV): Direct-acting antiviral combination therapy is widely available for HCV. Ideally, patients with HCV should be treated prior to lung transplant; however, patients with a detectable HCV viral load without significant liver fibrosis may be treated after lung transplant.
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Human immunodeficiency virus (HIV): Case series have demonstrated comparable 1-year and 5-year survival for HIV-infected lung transplant recipients with CD4+ lymphocyte counts above 200/mm3 and HIV viral loads below 20 copies/ml.
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Drug-drug interactions require expertise and careful coordination, and antiretroviral regimens free from efavirenz or ritonavir are recommended.Psychosocial risk factors
The psychosocial evaluation of lung transplant candidates encompasses assessment of psychological function, neuropsychiatric function, social support, substance use, transplant knowledge, and behavioral adherence.
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Despite wide recognition of the importance of psychosocial functioning for favorable lung transplant outcomes, few psychosocial contraindications are considered absolute. These include non-adherence to medical treatment, progressive cognitive impairment, and active substance use (Table 2). Importantly, psychosocial data are probabilistic by nature and therefore must not be interpreted in isolation. Transplant teams should feel empowered to use their own discretion to make informed decisions regarding patient selection with attention to the dangers of implicit bias against subsets of the population.Non-adherence: Repeated episodes of non-adherence without evidence of improvement are considered a contraindication for adult patients. For pediatric and young adult patients, ongoing assessment of non-adherence should occur as they progress through different developmental stages.
Pre-transplant cognitive impairment may impact medical decision-making, consent, and self-management capabilities. Dementia, which has become more common as candidate age has increased, is considered a contraindication, particularly progressive forms.
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Dementia has been associated with adverse post-operative outcomes.90
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, - Sher Y
- Mooney J
- Dhillon G
- Lee R
- Maldonado JR.
Delirium after lung transplantation: Association with recipient characteristics, hospital resource utilization, and mortality.
Clin Transplant. 2017; 31 (Epub 2017 Apr 11. PMID: 28314081; PMCID: PMC5509889)https://doi.org/10.1111/ctr.12966
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Other forms of cognitive dysfunction among individuals with advanced pulmonary disease may be amplified by hypoxemia or polypharmacy, and may improve post-transplant in some cases.94
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Affective and anxiety disorders may affect peri-operative outcomes and quality of life. Depressive symptoms prior to transplant have been linked to poorer transplant outcomes.
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The active use of psychotropic medications among candidates should not constitute a contraindication, but careful examination of potential interactions between psychotropic and transplant-specific medications should be conducted.Adequate support and caregiving in both the pre- and post-operative period are critical for success with lung transplant, and lack of support may increase risk of non-adherence and post-transplant mortality.
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Transplant centers are encouraged to consider socioeconomic status within the broader context of the patient's support system and psychological resources in order to identify patients requiring enhanced surveillance and support. However, socioeconomic factors should not warrant exclusion from candidacy.Substance use disorders: Patients should be assessed for active substance use disorders and where indicated engage in treatment prior to lung transplantation. Based on medical stability, this may constitute a provision of transplant listing. At the time of evaluation and then serially during the pre-transplant period, blood and urine testing may be used to verify abstinence from substances.
Nicotine: Lung transplant candidates must demonstrate abstinence from use of all tobacco and nicotine products (including nicotine replacement therapy) prior to transplant (e.g., with serial nicotine and cotinine screening).
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A short duration of abstinence (e.g., ≤ 6 months) and exposure to second-hand smoke confer a higher risk for relapse; duration of cessation should take into account the patient's medical acuity and stability.86
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Education on the importance of abstinence from all nicotine products (e.g., vaping), as well as limiting environmental or passive exposure to these products, should occur before referral for transplant and continue after transplant.15
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Cannabis: Inhaled cannabis use must be ceased prior to lung transplant.
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, National Academies of Sciences E, Medicine, Health
The National Academies Collection: Reports funded by National Institutes of Health. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research.
The National Academies Collection: Reports funded by National Institutes of Health. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research.
National Academies Press (US) Copyright 2017 by the National Academy of Sciences,
Washington (DC)2017
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Orally consumed cannabis should only be used prior to transplant if recommended by a medical provider, and if approved by the lung transplant team. Orally consumed cannabinoids, including those prescribed (e.g., dronabinol), may cause positive urine drug tests, complicating routine drug screening efforts, and if continued post-transplant, cannabis has the potential to interact with immunosuppression medications.120
Opioids: The safety of pre-lung transplant opioid use on transplant outcomes has not been widely studied.
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The risk and benefit of opioids prescribed to lung transplant candidates to palliate symptoms of pain or dyspnea should be considered on an individual basis. Medication assisted treatment (e.g., buprenorphine, naltrexone, methadone) for opioid use disorder has not been studied in advanced lung disease patients, and consultation with a psychiatrist or addictions specialist may be indicated in such cases.Pediatric considerations
Timing of referral: Although referral for pediatric patients should rely on similar principles as for adults, the wait time for children and infants may be longer than for adults due to the challenge of acquiring suitable sized organs. For infants < 2 years, the potential opportunity to use ABO incompatible donor lungs has expanded the pool of donor lungs.
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The recognition of unique and sometimes challenging aspects of pediatric recipients is crucial for their prolonged survival. Therefore, pediatric lung transplant candidates should be referred early and reviewed in detail in order to maximize their chances of having a successful transplant.Indications for lung transplant in children: CF remains the leading indication for lung transplant in children aged 6-17 years; however, the number of candidates with idiopathic pulmonary arterial hypertension (IPAH) is increasing, and it is currently the most common indication for those 1-5 years of age.
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For infants (<1 year) surfactant protein B deficiency and pulmonary hypertension (which is usually due to congenital heart disease, not IPAH) are the primary indications for lung transplant.- Hayes Jr., D
- Cherikh WS
- Chambers DC
- et al.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Twenty-second pediatric lung and heart-lung transplantation report-2019; Focus theme: donor and recipient size match.
J Heart Lung Transplant. 2019; 38: 1015-1027
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Other infant and childhood indications include adenosine triphosphate binding cassette protein member A3 deficiency, alveolar capillary dysplasia with misalignment of pulmonary veins, childhood interstitial lung disease, and bronchiolitis obliterans.- Hayes Jr., D
- Cherikh WS
- Chambers DC
- et al.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Twenty-second pediatric lung and heart-lung transplantation report-2019; Focus theme: donor and recipient size match.
J Heart Lung Transplant. 2019; 38: 1015-1027
Consent: Children and their families require developmentally appropriate education and a child must consent/assent at the level of their understanding.
Adherence: In adolescence, nonadherence can be a significant challenge both pre- and post-transplant, potentially resulting in poor outcomes.
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Therefore, non-adherence must be evaluated in detail during the referral and evaluation process to determine if it is a modifiable factor.Transitions of care: The transition from pediatric to adult care while on the waiting list or after transplant may be problematic and careful planning is recommended.
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Growth: In the pre-transplant period optimizing growth and nutritional status in children is important, not only as preparation for the operation, but also because growth may be attenuated by medications post-transplant
Extracorporeal Membrane Oxygenation (ECMO): In the past, ECMO was considered a relative contraindication but more recently ECMO as a bridge to transplant in children has become more acceptable.
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Disease specific considerations in pediatric patients
CF in pediatric patients: Young adolescent females with a rapid decline in pulmonary function tests should be referred early due to their poor prognosis.
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The US CF Foundation guidelines for lung transplant referral state patients with CF <18 years of age should be referred no later than when FEV1 is < 50% predicted and rapidly declining (> 20% relative decline within 12 months); or FEV1 is < 50% predicted with markers of shortened survival (low 6-minute walk, hypoxemia, hypercarbia, pulmonary hypertension); or FEV1 is < 40% predicted.134
Children with CF should be listed for lung transplantation when FEV1 is <30% predicted.134
Pulmonary arterial hypertension (PAH) in pediatric patients: Specific guidelines for diagnosis and treatment of pediatric patients with PAH were developed in 2013.
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According to the latest guidelines from the European Pediatric Pulmonary Vascular Disease Network (EPPVDN), patients are stratified into low or high-risk categories indicating their prognosis.137
Determinants of risk are based on clinical evidence of right ventricular dysfunction, progression of symptoms, syncope, growth, WHO functional class, serum B-type natriuretic peptide (BNP) or N-terminal (NT)-pro hormone BNP (NT-proBNP), echocardiography, and invasive measures of hemodynamics (cardiac index, mean pulmonary artery pressure, mean right atrial pressure and pulmonary vascular resistance index).137
Patients should be referred to a lung transplant center for evaluation when they remain in an intermediate- or high-risk category despite maximal PAH therapy (i.e., triple therapy). However, early referral is preferable especially in children with IPAH. Potts shunt or atrial septostomy (in patients with functional class III and IV and recurrent syncope) may be considered as a bridge to transplant in some centers, but this remains controversial.136
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Children with PAH in the high-risk category and on optimal therapy without improvement should be listed for lung transplantation.Other diseases: Alveolar capillary dysplasia, pulmonary vein stenosis refractory to intervention, and pulmonary veno-occlusive disease (PVOD) are all rare entities with a very poor prognosis for which urgent evaluation and listing for lung transplantation should be considered.
Surgical considerations
Previous chest surgery: Previous chest surgery, particularly pleurodesis, is associated with greater blood loss and early post-operative morbidity such as renal dysfunction and primary graft dysfunction. Review of the most recent literature demonstrates that although up to 45% of lung transplant recipients have undergone previous cardiothoracic procedures, no survival difference has been observed.
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Prior lung transplant, especially for those who have developed restrictive allograft syndrome, confers a higher risk for poor survival.1
,- Chambers 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: 1042-1055
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Pneumothorax / Pleurodesis: When possible, management of a pneumothorax in a patient who may be a potential lung transplant candidate should be discussed with a transplant center. Although avoidance of talc pleurodesis is preferred, it is not a contraindication and the patient should be given the best immediate management.
Lobar lung transplant: Potential candidates with small chest size may be candidates for lobar lung transplant. While early complications may be higher, the 1- and 3- year survival may be comparable to conventional transplant, suggesting lobar lung transplant may be an acceptable option.
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Other considerations: Significant chest wall abnormalities, spinal deformities, or mediastinal fibrosis require individualized evaluation to determine surgical feasibility and degree of restriction anticipated post-transplant.
Bridge to transplant (BTT)/extracorporeal life support (ECLS)
With the implementation of urgency-based lung allocation systems in many countries, the use of ECLS as a BTT has become a more viable option. Technological advances have improved the efficacy of BTT devices, especially ECMO, leading to its more prevalent use in transplant centers. In general, success of BTT is dependent on center experience with ECLS and lung transplant in general.
143
,144
Indications for ECLS include hypercapnic respiratory failure, hypoxic respiratory failure, and right ventricular failure.143
,144
A care plan for the use of BTT should be determined with multidisciplinary input at the time of listing as clinical deterioration can be rapid and not all candidates may be candidates for ECLS as BTT. Extra-thoracic organ dysfunction may be a contraindication to BTT with an exception for patients with pulmonary hypertension and right ventricular dysfunction where renal and hepatic dysfunction is often reversed after ECLS initiation. Uncontrolled sepsis, older age, lack of center experience with BTT strategies, and patients who have not been considered previously for transplant, represent scenarios fraught with the likelihood of poor outcomes.The timing for ECLS is determined by patient condition and the circumstances surrounding the likelihood for donor organ availability. The following considerations factor into the decision to initiate ECLS: oxygen saturation less than 90% with use of high flow non-invasive oxygenation devices; hemodynamic instability; use of positive pressure ventilation that could lead to further lung injury and secondary organ dysfunction; and inability of candidate to perform adequate physical therapy with current support. After initiation of ECLS, candidates should preferably be awake, carefully mobilized, and monitored continually for development of clinical characteristics that would negatively impact transplant candidacy.
Lung re-transplantation
Approximately 5% of all lung transplants performed are re-transplants.
1
The outcomes after re-transplants are inferior compared to first lung transplants, particularly if the re-transplant is done within the first year after the original transplant or for patients with restrictive allograft syndrome (RAS).- Chambers 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: 1042-1055
1
,- Chambers 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: 1042-1055
139
,140
,145
, 146
, 147
, 148
, 149
Several studies, however, have found acceptable results for carefully selected recipients.140
,146
,150
,151
In the pre-transplant evaluation of such patients, particular emphasis should be focused on understanding the possible reasons for the graft failure, such as alloimmunization, poor adherence, GER, or repeated infections.86
,152
Multi-organ transplantation
Multi-organ transplantation is considered for patients in whom survival with isolated lung transplant is unlikely without the simultaneous transplant of another organ or in those for whom significant post-transplant organ dysfunction is anticipated in the event of lung transplant alone. Multi-organ transplant accounts for approximately 1.6% of lung transplants.
153
Multi-organ transplant candidates have a higher waiting list mortality than individuals listed for single organ transplant- Chambers DC
- Cherikh WS
- Goldfarb SB
- et al.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-fifth adult lung and heart-lung transplant report-2018; Focus theme: multi-organ transplantation.
J Heart Lung Transplant. 2018; 37: 1169-1183
154
; however, recipients who survive the difficult peri-operative period experience significant survival benefit, with favorable long-term survival.153
The best outcomes from multi-organ transplant are achieved by specialized high-volume institutions.- Chambers DC
- Cherikh WS
- Goldfarb SB
- et al.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-fifth adult lung and heart-lung transplant report-2018; Focus theme: multi-organ transplantation.
J Heart Lung Transplant. 2018; 37: 1169-1183
155
Heart-lung transplant: The primary indication for heart-lung transplant is pulmonary hypertension, either secondary to idiopathic pulmonary arterial hypertension or congenital heart disease (CHD).
153
Criteria for heart-lung transplant listing described in a previous version of this document include the presence of New York Heart Association (NYHA) functional class IV symptoms despite maximal medical management, a cardiac index below 2 l/min/m2, and a mean right atrial pressure above 15 mmHg- Chambers DC
- Cherikh WS
- Goldfarb SB
- et al.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-fifth adult lung and heart-lung transplant report-2018; Focus theme: multi-organ transplantation.
J Heart Lung Transplant. 2018; 37: 1169-1183
4
; however, the decision about whether to list a patient for heart-lung transplant remains difficult. Candidates free from complex CHD or left ventricular compromise can achieve comparable outcomes with isolated bilateral lung transplant.156
, 157
, 158
, 159
Similarly, patients with advanced lung disease and cardiac pathology amenable to surgical repair may be candidates for lung transplant concurrent with the appropriate corrective cardiac procedure.160
Lung-liver transplant: Lung-liver transplant is a therapeutic option for advanced lung disease associated with cirrhosis (e.g. CF, alpha-1 antitrypsin deficiency), and end-stage liver disease with pulmonary compromise. Lung-liver transplant should be considered for patients meeting lung transplant listing criteria with biopsy proven cirrhosis and a portal gradient >10 mmHg. There is some evidence that survival is non-inferior for lung-liver transplant vs isolated lung transplant in recipients with a LAS <50; however, higher mortality amongst recipients with higher LAS and Model for End-Stage Liver Disease (MELD) scores suggests there may be a ceiling beyond which patients are too sick to achieve a survival benefit from lung-liver transplant.
161
,162
Severely impaired liver synthetic function with an albumin <2.0 g/dl, INR >1.8 or the presence of severe ascites or encephalopathy should be considered contraindications.163
In addition, one study has suggested there may be no survival advantage with lung-liver transplant when compared to matched single-organ lung transplant recipients with an equivalent degree of liver dysfunction, suggesting a need for more precise criteria to determine optimal lung-liver transplant candidates.164
Lung-kidney transplant: A significant and increasing proportion of potential lung transplant candidates have established renal dysfunction. Despite being sicker at baseline, patients with renal dysfunction who undergo lung-kidney transplant have similar 1-year and 5–year survival when compared to recipients of isolated lung transplant, but it is unclear whether simultaneous lung-kidney transplant can completely attenuate the increased risk of mortality in this population.
17
,165
Disease specific considerations
In addition to the general considerations and risk factors that may affect an individual's candidacy for lung transplant, there are important disease specific considerations that should guide referral and listing.
Chronic obstructive pulmonary disease (COPD)
Prognostic models that can be used to determine the appropriate timing of listing for lung transplant for COPD patients are inherently imprecise as survival is highly variable even among patients with advanced disease. In general, multidimensional models have proven to be more robust predictors of mortality than single parameters. The most familiar of these is the BODE index [BMI, airflow limitation (forced expiratory volume in one second), dyspnea and 6-minute walk distance], which has been externally validated in at least 13 additional cohorts following the original derivation. The BODE index has been cited as the prognostic model of choice by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), and it formed the basis for listing recommendations in the 2014 ISHLT candidate selection guidelines.
4
,166
, 167
, 168
The calibration of the original BODE index (i.e., the degree to which the predicted mortality risk agrees with observed mortality) has been called into question by a number of subsequent studies. In particular, two studies looked specifically at the ability of the BODE index to predict mortality among lung transplant candidates with COPD.
169
,170
Both found that the BODE index overestimated mortality. In the larger of the two studies, survival of 4,377 lung transplant candidates with COPD in the OPTN/UNOS database was compared to that of the cohort of COPD patients that served as the validation group in the original BODE publication.170
Median survival of patients in the fourth quartile of BODE scores7
, 8
, 9
, 10
was 59 months in the transplant candidate cohort and 37 months in the original BODE cohort. The poor calibration of the BODE index among transplant candidates likely reflects the marked differences in age, comorbidities, and active smoking in this carefully screened population compared to the general population included in the original validation cohort. BODE index has also been shown to overestimate mortality among the subset of COPD patients with alpha-1-antitrypsin deficiency, likely for similar reasons.171
Acknowledging the calibration issues, a fourth quartile BODE score
7
, 8
, 9
, 10
still appears to identify a group of transplant-eligible patients whose predicted median survival without transplant is less than the observed median survival of patients with COPD post-transplant (6.0 years).172
It therefore stands as the best guideline for listing patients. An FEV1 < 20% predicted is an additional consideration in listing COPD patients, as this has been identified as a threshold below which transplant is likely to confer a survival advantage.173
Other factors associated with increased mortality that may influence listing are pulmonary hypertension, chronic hypercapnia, and severe acute exacerbations (e.g., requiring an emergency department visit or hospitalization.)174
, 175
, 176
Patients with advanced but not imminently life-threatening COPD, characterized by BODE scores in the range of 5-6 and FEV1 20%-25% predicted, may benefit from referral to a transplant center for initial consultation even if immediate listing is not anticipated. Additional parameters that have been identified as predictors of increased mortality (although not fully validated) that should prompt referral when present include an increase in BODE index score > 1 over past 24 months and pulmonary artery to aorta diameter > 1 on CT scan.
175
,177
,178
While DLCO has not been shown to be an independent predictor of mortality in COPD, a low DLCO has been associated with increased COPD symptoms, reduced exercise performance, and severe exacerbation risk, and thus, also may prompt consideration of referral.179
,180
The patient's perception of an unacceptably poor quality of life may also be a consideration, albeit not the principal driver for referral, given the significant symptomatic benefits that transplant offers this patient population even in the face of an uncertain survival benefit.Special considerations in COPD: Lung volume reduction (LVR), performed by either surgical or bronchoscopic approach, is an option for a subset of COPD patients with advanced emphysema who meet strict selection criteria. These procedures have been associated with improved lung function, exercise capacity, and quality of life.
181
, 182
, 183
Survival benefit has been demonstrated in a select group of patients with upper lobe predominant emphysema and low exercise capacity who undergo surgical LVR.183
Notably, outcomes are not uniformly beneficial even among carefully selected candidates.181
, 182
, 183
For patients whose disease does not warrant imminent listing for lung transplant, LVR should be considered, as a successful outcome can postpone the need for transplant, and the associated improvement in functional and nutritional status can optimize the patient's suitability as a future transplant candidate.
184
, 185
, 186
, 187
Prior LVR surgery can lead to formation of pleural adhesions, which can pose technical challenges to the surgeon at the time of transplant. Several published series document increased operative times and peri-operative bleeding in transplant recipients who had previously undergone LVR surgery.185
,188
,189
Although post-transplant survival was not impacted in some studies, one study reported that 1-, 5-, and 10-year survival was lower in individuals who had undergone LVR surgery prior to transplant when compared to individuals who had undergone transplant alone.185
,188
, 189
, 190
Interstitial lung disease (ILD)
Idiopathic pulmonary fibrosis (IPF), the prototype of fibrotic ILDs, carries a prognosis of 3-5 years survival after diagnosis when untreated. Two anti-fibrotic medications (nintedanib and pirfenidone) have been shown to reduce the rate of forced vital capacity (FVC) decline and slow disease progression in patients with a definite usual interstitial pneumonia (UIP) pattern and with a probable UIP pattern on high resolution CT (HRCT).
191
, 192
, 193
Though the studies were not powered to show an effect on mortality, post-hoc analysis, registry data and computational models all confirm a survival benefit and likely also a decrease in the number of acute exacerbations, which are associated with a high mortality.191
,192
,194
Thus, since the last version of this document, the use of these medications has become more widespread and the decision regarding the timing of listing for lung transplant has become more challenging. With the unpredictable nature of acute exacerbations, it remains advisable to refer patients with IPF early for lung transplant evaluation (Table 3).Table 3Updated Consensus Statements
| Each statement listed as a 2021 consensus statement reflects expert synthesis of the current literature with additional rationale provided in the accompanying text. The statements are all based on consensus reached by the committee (24 members) with an a priori threshold of >80% agreement on consensus statements. | ||
| GENERAL CONSIDERATIONS | ||
| 2014 Consensus Statement | 2021 Consensus Statement | Consensus N (%) |
Lung transplantation should be considered for adults with chronic, end-stage lung disease who meet all the following general criteria:
| Lung transplantation should be considered for adults with chronic, end-stage lung disease who meet all the following general criteria:
| 24 (100%) |
| Prior to determining that a patient is not a candidate for lung transplantation, referring providers should communicate directly with at least one lung transplant program with experience with the candidate's potential contraindication(s). | 24 (100%) | |
| Early referral is recommended to facilitate transplant education for the patient and caregivers, an initial assessment of barriers to transplant, and determination of timing for full evaluation with specific recommendations for optimization of candidacy. | 24 (100%) | |
| Determination of candidacy requires a detailed evaluation not only to select appropriate candidates, but also to optimize each individual's status to provide them with the best chance for a successful outcome. | 24 (100%) | |
| Individual transplant candidacy at a particular institution depends on that center's expertise for management of patients who have risk factors posing high or substantially increased risk. | 24 (100%) | |
| Decision making regarding timing of listing for transplant should take into consideration results of the full evaluation, including disease severity and trajectory, estimated wait time for donor organ(s) and survival time without transplant, and candidate's readiness for transplant. | 24 (100%) | |
| Just as the decision to list is carefully considered, interval reassessment for continued listing should take place to evaluate the risks and benefits of transplant when considering any changes to the candidate's status that may impact predicted perioperative or post-transplant outcomes. | 24 (100%) | |
| When referring for lung transplant evaluation, consider simultaneous referral to palliative care to provide decision support and treatment selection that is consistent with goals of care throughout the transplant evaluation, listing, surgery, and post-transplant. | 23 (96%) | |
| PEDIATRIC CANDIDATE RECOMMENDATIONS | ||
| 2014 Consensus Statement | 2021 Consensus Statement | Consensus N (%) |
| Timing of Referral | Timing of Referral | |
|
| 24 (100%) |
| Potential pediatric candidates should be referred to a transplant center as early as possible, to minimize waitlist mortality, especially in younger children as wait times may be longer. | 24 (100%) | |
| Ongoing assessment of non-adherence should occur for pediatric patients as they move through different stages of development. | 24 (100%) | |
| We recommend that referring physicians periodically discuss and update referral practices with their partnering transplant center. | 24 (100%) | |
| Timing of Listing | ||
In addition to general recommendations for adults, considerations for listing children for lung transplant include the following:
| 24 (100%) | |
| Transition from pediatric to adult care while on the waiting list needs careful planning, timing, and ongoing communication | 24 (100%) | |
| In pediatric candidates, growth and nutritional status should be carefully monitored. | 24 (100%) | |
| Extracorporeal life support may be an acceptable bridge to transplant in appropriately selected pediatric candidates at centers with expertise. | 24 (100%) | |
| LUNG RE-TRANSPLANTATION | ||
| 2014 Consensus Statement | 2021 Consensus Statement | Consensus N (%) |
| The timing of re-transplant is a complex issue and requires consideration of the rate of deterioration, time since initial transplant, the need for supportive therapies and donor lung availability, which may be limiting in some cases. | 23 (95%) | |
Table 3 (Continued) | Survival after re-transplant is inferior to that seen with the primary operation and should only be undertaken in carefully selected candidates. | 24 (100%) |
| In the evaluation of patients being considered for lung re-transplant, particular emphasis should be focused on understanding the possible reasons for the graft failure, such as alloimmunization, poor adherence, gastroesophageal reflux, or repeated infections. | 23 (96%) | |
| MULTI-ORGAN TRANSPLANTATION | ||
| 2014 Consensus Statement | 2021 Consensus Statement | Consensus N (%) |
| Heart-lung and other multi-organ transplantation should be limited to centers with experience in such procedures and where specialists are available to manage each of the transplanted organs. | 24 (100%) | |
| Candidates should meet the criteria for lung transplant listing and have significant dysfunction of one or more additional organs, or meet the listing criteria for a non-pulmonary organ transplant and have significant pulmonary dysfunction. | 24 (100%) | |
| Waiting times are likely to be longer and the likelihood of receiving a transplant is reduced when an individual requires more than one organ. Thus, referral should occur earlier in the disease course if multi-organ transplantation may be considered. | 24 (100%) | |
| DISEASE SPECIFIC CANDIDATE RECOMMENDATIONS | ||
|---|---|---|
| Chronic Obstructive Pulmonary Disease (COPD) | ||
| 2014 Consensus Statement | 2021 Consensus Statement | Consensus N (%) |
| Timing of Referral | Timing of Referral | |
|
| 24 (100%) |
| 23 (96%) | |
| Timing of Listing | Timing of Listing | |
|
| 24 (100%) |
| Interstitial Lung Disease (ILD) | ||
| 2014 Consensus Statement | 2021 Consensus Statement | Consensus N (%) |
| Timing of Referral | Timing of Referral* | |
|
| 22 (92%) |
|
| 24 (100%) |
|
| 24 (100%) |
|
| 24 (100%) |
|
| 24 (100%) |
| 24 (100%) | |
| Timing of Listing | Timing of Listing* | |
|
| 24 (100%) |
| *NOTE: For patients with concomitant emphysema, FVC may be a less reliable parametear. | ||
| Cystic Fibrosis (CF) | ||
| 2014 Consensus Statement | 2021 Consensus Statement | Consensus N (%) |
| Timing of Referral | Timing of Referral | |
| Referral for lung transplantation should occur for an individual with CF meeting any of the following criteria despite optimal medical management including a trial of elexacaftor / tezacaftor / ivacaftor if eligible:
| 24 (100%) |
| Timing of Listing | Timing of Listing | |
| Listing for lung transplantation should occur for an individual with CF meeting any of the above referral criteria in combination with any of the following:
| 24 (100%) |
| Additional Recommendations | Additional Recommendations | |
| Patients with CF who are referred for transplantation should be evaluated for NTM pulmonary disease. Patients with NTM disease who are being evaluated for transplantation should have the organism confirmed according to microbiology guidelines and begin treatment before transplant listing. | For lung transplant candidates with CF, regular communication between CF and transplant centers is encouraged (at least every six months and with major clinical changes) to review disease trajectory, proactive management of potential barriers to transplantation, along with listing status and timing including in relationship to treatment with elexacaftor / tezacaftor / ivacaftor or other novel CF medications. | 24 (100%) |
| Treatment should be by, or in collaboration with, a physician experienced in the treatment of such patients Progressive pulmonary or extrapulmonary disease secondary to NTM despite optimal therapy or an inability to tolerate optimal therapy is a contraindication for trans-plant listing. All patients with CF referred for transplantation should be evaluated for the presence of B cepacia. | In individuals with CF, a lower threshold for both lung transplant referral and listing should be considered in females and those with short stature, diabetes, or increasing antibiotic resistance including infection with Burkholderia cepacia complex or nontuberculous mycobacteria. | 24 (100%) |
| All transplant candidates with CF should be evaluated for Burkholderia cepacia complex, nontuberculous mycobacteria, and fungal pathogens | 24 (100%) | |
| Patients with species other than B cenocepacia do not constitute an increased risk for mortality after transplantation and can be listed, provided that other criteria are met. Patients with B cenocepacia have an increased risk of mortality secondary to recurrent disease after trans-plantation. It is recommended that centers continuing to accept such patients should have an active research program assessing novel approaches to prevent and control recurrent disease and should be experienced in management of these patients. A full discussion with the patients of the increased risk associated with these infections should occur. | ||
| Non-CF Bronchiectasis | ||
| 2014 Consensus Statement | 2021 Consensus Statement | Consensus N (%) |
| For individuals with non-CF bronchiectasis, similar criteria as with CF for referral and listing for lung transplantation is reasonable, though providers should recognize that prognosis is highly variable with many patients experiencing a more stable course. | 24 (100%) | |
| Pulmonary Arterial Hypertension (PAH) | ||
| 2014 Consensus Statement | 2021 Consensus Statement | Consensus N (%) |
| Timing of Referral | Timing of Referral | |
|
| 24 (100%) |
| Timing of Listing | Timing of Listing | |
|
| 24 (100%) |
| Lymphangioleiomyomatosis (LAM) | ||
| 2014 Consensus Statement | 2021 Consensus Statement | Consensus N (%) |
| Timing of Referral | ||
Referral for lung transplantation evaluation should occur for an individual with LAM who has any of the following despite mTOR inhibitor therapy:
| 24 (100%) | |
| Timing of Listing | ||
| Listing for lung transplantation should occur for an individual with LAM who meets the above referral criteria and has evidence of disease progression despite mTOR inhibitor therapy. | 24 (100%) | |
| Cessation of mTOR inhibitor therapy should occur at the time of transplant but cessation should not be required for placement on the waiting list. It may be preferable to use everolimus and target trough levels in the lower therapeutic range for patients on the waiting list. | 23 (96%) | |
| Thoracic Malignancy | ||
| 2014 Consensus Statement | 2021 Consensus Statement | Consensus N (%) |
| Lung transplant should be limited to very select cases of lung-limited adenocarcinoma in situ, minimally invasive adenocarcinoma, or lepidic predominant adenocarcinoma for patients in whom (1) surgical resection is not feasible either because of multifocal disease or significant underlying pulmonary disease; (2) multifocal disease has resulted in significant lung restriction and respiratory compromise; (3) medical oncology therapies have failed or are contraindicated; and (4) lung transplant is expected to be curative. | 22 (92%) |
| Acute Respiratory Distress Syndrome (ARDS) | ||
| 2014 Consensus Statement | 2021 Consensus Statement | Consensus N (%) |
| Timing of Listing and Referral | ||
| Persistent requirement for mechanical ventilatory support and /or ECLS without expectation of clinical recovery and with evidence of irreversible lung destruction. | 24 (100%) | |
Abbreviations: ARDS, Acute Respiratory Distress Syndrome; BMI, Body Mass Index; CF, Cystic Fibrosis; COPD, Chronic Obstructive Pulmonary Disease; DLCO, diffusion capacity of carbon monoxide; ECLS, Extracorporeal Life Support; EPPVDN, European Pediatric Pulmonary Vascular Disease Network; ESC/ERS, European Society of Cardiology/European Respiratory Society; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; ILD, Interstitial Lung Disease; LAM, Lymphangioleiomyomatosis; LVRS, Lung volume reduction surgery; NTM, Non-tuberculous mycobacteria; PA, pulmonary arterial; PCH, Pulmonary capillary hemangiomatosis; PVOD, Pulmonary veno-occlusive disease; REVEAL, Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management; UIP, usual interstitial pneumonia; WHO, World Health Organization.
Patients with non-IPF ILDs may also experience a disease course similar to IPF.
195
, 196
, 197
, 198
, 199
, 200
Recently, 3 trials have shown a response to anti-fibrotic therapy in patients with other forms of progressive fibrotic ILD, including chronic hypersensitivity pneumonitis, autoimmune-ILD, idiopathic non-specific interstitial pneumonitis, unclassifiable idiopathic interstitial pneumonitis, and a group of other rarer fibrotic ILDs.198
,199
,201
,202
Importantly, in two of these trials, patients were included on the basis of disease progression despite standard management.198
,199
Combining two out of three domains (FVC decline, HRCT progression, or increased symptoms) identified patients who showed a FVC decline and a response to therapy similar to IPF.198
,203
These results may change the treatment paradigm of fibrotic ILDs, so that management decisions will be based on disease behavior as well as histological or HRCT patterns.- Wells AU
- Flaherty KR
- Brown KK
- et al.
INBUILD trial investigators
Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial.
Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial.
Lancet Respir Med. 2020; 8: 453-460
197
Consistent clinical predictors of survival in non-IPF ILDs include FVC and DLCO decline, hospitalization, frailty, oxygen use and symptoms; thus, timing of referral and listing for lung transplant should take these factors into account (Table 3).204
, 205
, 206
, 207
, 208
, 209
In patients with concurrent emphysema, a decline in FVC is a less reliable parameter to detect progression of fibrosis, and other markers such as progression of disease on CT scan or DLCO, or development of secondary pulmonary hypertension, may be more useful.210
,211
Predicting prognosis for individual patients with ILD remains difficult. Signs of pulmonary hypertension and right ventricular failure, or the occurrence of pneumothorax have been associated with worse outcomes in ILD.
212
, 213
, 214
, 215
UIP pattern on HRCT is also associated with worse outcomes in many ILDs, although for rheumatoid arthritis-ILD some debate exists on pattern versus extent of involvement on HRCT.197
,216
Promising results in novel computer-based imaging analysis need further prospective development and validation in larger data sets., 218
, 219
Serum and genetic biomarkers have been studied in IPF, but data are also now becoming available in other ILDs.220
, 221
, 222
, 223
, 224
Whilst some biomarkers are promising, none has been validated for clinical application.225
Different composite predictors of outcome have been developed in the past years; however, clinical uptake and external validation is limited.226
, 227
, 228
, 229
, 230
, 231
, - Sharp C
- Adamali HI
- Millar AB.
A comparison of published multidimensional indices to predict outcome in idiopathic pulmonary fibrosis.
ERJ Open Res. 2017; 3 (00096-2016PMID: 28326312; PMCID: PMC5349096)https://doi.org/10.1183/23120541.00096-2016
232
At this point, no biomarker or clinical prediction algorithm has been established as a reliable predictor for disease outcome or response to therapy in ILD.233
Therefore, early referral is still recommended to reduce the likelihood that a potentially eligible patient may miss the opportunity for lung transplant. Timing of listing should be discussed with each individual patient considering such factors as rate of progression despite standard management, expected prognosis, age, comorbidities, and transplant risks.Patients with ILDs that may require special consideration include patients with familial fibrosis, antineutrophil cytoplasm antibody (ANCA) associated vasculitides, sarcoidosis, connective tissue disease, or Heřmanský–Pudlák syndrome.
234
, 235
, 236
, 237
Transplant challenges in these patients relate to potential extrapulmonary involvement which may complicate assessment and acceptance for transplant.38
,238
,239
Specific transplant considerations for patients with CTD-ILD are due to be published as part of a separate ISHLT consensus document. Patients with possible familial pulmonary fibrosis should undergo assessment for clinical manifestations of telemeropathy, with particular attention to evaluation for hematologic abnormalities (see above) and liver cirrhosis. Patients with sarcoidosis may need additional evaluation to examine the extent of possible cardiac involvement and to exclude malignancy as an etiology for lymphadenopathy.For patients with ILD on the lung transplant waiting list, both nintedanib and pirfenidone may be continued until transplant. Although mechanistically anti-fibrotic medications could affect wound healing, recent case series have shown no impaired wound or anastomotic healing and no increase in bleeding risk in patients on these medications.
240
,241
- Leuschner G
- Stocker F
- Veit T
- et al.
Outcome of lung transplantation in idiopathic pulmonary fibrosis with previous anti-fibrotic therapy.
J Heart Lung Transplant. 2017 Jul 5; (S1053-2498(17)31886-7Epub ahead of print. PMID: 28734935)https://doi.org/10.1016/j.healun.2017.07.002
Cystic fibrosis (CF)
FEV1 has been the best individual predictor of mortality in CF, with studies from the 1990s demonstrating a median survival of 2-4 years after reaching an FEV1 < 30% predicted.
242
, 243
, 244
More recent studies have shown improved outcomes in advanced CF lung disease, including an analysis demonstrating a median survival of 6.6 years in patients in the U.S. with FEV1 < 30% predicted.245
Moreover, while data are lacking, outcomes may further improve with highly effective CF transmembrane conductance regulator (CFTR) modulators, where early clinical experience suggests that many individuals approaching lung transplant achieve disease stabilization or even improvement with the combination of elexacaftor, tezacaftor, and ivacaftor.Despite improved overall outcomes, many individuals with advanced CF lung disease remain at risk of short-term mortality. A 2017 study demonstrated a 10% risk of death each year after reaching an FEV1 < 30%, with many patients dying soon after reaching this threshold.
245
Adjusted predictors of death included supplemental oxygen, Burkholderia cepacia complex, body mass index (BMI) ≤ 18 kg/m2, female sex, insulin-requiring diabetes, and ≥ 1 exacerbation per year. Additional risk factors for mortality in those with severely compromised lung function include FEV1< 25% predicted, rapid decline in FEV1, PaCO2 > 50 mmHg, impaired functional status, and pulmonary hypertension.244
,246
, 247
, 248
, 249
, 250
, 251
Independent of FEV1, the following factors have been associated with increasing risk of disease progression or death: frequent or severe exacerbations, massive hemoptysis requiring bronchial artery embolization, pneumothorax, malnutrition, low 6-minute walk distance, and younger age upon development of advanced disease.247
,252
, 253
, 254
, 255
, 256
, 257
, 258
, 259
, 260
Composite scores have also been developed including one combining FEV1 (>60% vs 30%-60% vs <30% predicted), BMI (>18.5 vs 16-18.5 vs <16 kg/m2), presence of Burkholderia cepacia complex, intravenous antibiotic courses (0, 1-2, >2 per year), history of hospitalizations, oral steroids, long-term oxygen, and need for non-invasive ventilation.254
In this model a score of ≥ 4 was associated with a 55% risk of 3-year mortality, whereas a score of ≤ 2 carried only a 1% risk.Transplant referral guidelines were established by the CF Foundation for use by CF centers.
134
Because of difficulties in predicting survival and late or non-referral of potential candidates, major themes in these recommendations included pre-emptive discussion of transplant in all patients with advanced lung disease, proactive recognition of risk factors for disease progression, and early referral and improved communication with transplant centers.134
,261
These goals will continue to be important even in the era of highly effective CFTR modulators, particularly in patients who are ineligible for, cannot tolerate, or do not respond to such therapy, or if adverse long-term clinical effects arise. Predictors of survival with CF may need re-evaluation in the era of highly effective CFTR modulator therapy and new data may affect thresholds for referral and listing.Special considerations in cystic fibrosis: Several comorbidities should be considered when evaluating candidates with CF. Infection or colonization with multi-drug resistant organisms including Burkholderia cepacia complex, Pseudomonas aeruginosa, and nontuberculous mycobacteria (M. abscessus in particular) have been shown to increase the rate of lung function decline or death without transplant in advanced CF.
245
,247
,254
,258
,262
Implications of B. cenocepacia, M. abscessus, or L. prolificans are described above (infectious disease risk factors). Post-transplant infectious recolonization in CF is thought to be related to sinus or other upper airway reservoirs and is associated with increased risk of graft dysfunction.263
,264
Although data supporting pre-transplant sinus surgery are lacking, optimization of sino-nasal management prior to transplant should be thoroughly considered given the high incidence of sinus disease and potential post-transplant implications.264
, 265
, 266
, 267
Non-infectious comorbidities include malnutrition, which is common in CF patients approaching transplant and represents a potentially modifiable risk factor. A low BMI is associated with lung function decline and mortality in advanced CF lung disease.
245
Although low BMI has been associated with post-transplant mortality among CF patients, a recent analysis demonstrated a reasonable median post-transplant survival of 7.0 years in CF patients with pre-transplant BMI <17kg/m2, which was similar to other commonly transplanted non-CF cohorts.45
,268
Hepatobiliary disease is a less common complication that can impact candidacy and procedure choice. Cholestasis is almost universal among lung transplant candidates with CF; however, clinically important liver disease occurs in only 3%-5%, mostly before age 20 years.269
Data are limited on the impact of CF-associated liver disease on lung transplant outcomes; however, in cases of overt portal hypertension or synthetic dysfunction, combined lung-liver transplant has had comparable outcomes to lung transplant alone, particularly over the long-term.153
,- Chambers DC
- Cherikh WS
- Goldfarb SB
- et al.
The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-fifth adult lung and heart-lung transplant report-2018; Focus theme: multi-organ transplantation.
J Heart Lung Transplant. 2018; 37: 1169-1183
270
Finally, the risk of colorectal cancer is increased in CF compared to age-matched controls, and transplant programs should screen CF candidates with colonoscopy beginning at age 40 years based on the 2017 CF Foundation Guidelines.271
Non-cystic fibrosis bronchiectasis
Non-CF bronchiectasis represents 2.7% of all lung transplants reported to the ISHLT Registry between 1995and 2018.
1
Determining transplant timing is difficult due to the wide range of etiologies and demographics. Two non-CF bronchiectasis severity assessment tools were developed from the overall population (not limited to those with advanced lung disease): the FACED score [FEV1, Age, Chronic Pseudomonas aeruginosa, Extension to 1-2 lobes, Dyspnea by modified Medical Research Council scale] and the bronchiectasis severity index (BSI), which adds BMI and exacerbation frequency.- Chambers 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: 1042-1055
272
,273
The FACED score and BSI have been used to characterize prognosis and disease severity, respectively.272
,273
A high FACED score5
, 6
, Ethical 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/
7
has been associated with median survival of approximately 5.5 years. Older age and specific etiology appear to impact prognosis.Similar to CF, FEV1% predicted has been shown to be discriminating for mortality. One study demonstrated a 4-year mortality of 39% in non-CF bronchiectasis patients with FEV1 < 30% predicted.
273
Outcomes between CF and non-CF bronchiectasis, however, may not be the same in advanced disease populations. In a study evaluating survival among 2,112 patients who were listed but did not undergo transplant, multivariate Cox models identified a lower risk of death (HR 0.684, CI 0.475-0.985) and 5-year mortality of only 25% in the non-CF group despite similar lung function in the CF and the non-CF groups (FEV1 of 25.1% vs 27.1% predicted, respectively), leading the authors to propose different thresholds for transplant listing.274
Pulmonary arterial hypertension (PAH)
Early consideration of transplant should be emphasized for patients with PAH, as referral of patients at the onset of clinical deterioration may not provide enough time to complete the evaluation and to obtain a suitable donor organ.
275
This issue is of particular importance in countries which utilize a lung allocation score because it does not fully capture the waitlist mortality for individuals with PAH.276
, 277
, 278
, 279
, 280
Notably in allocation systems that use a high priority allocation for patients with PAH who are at imminent risk of death, improved waitlist survival and an increased rate of transplant has been observed.281
The 2014 ISHLT consensus document on the selection of lung transplant recipients recommended referral for transplant in patients with PAH when advanced symptoms are present despite escalation of therapy or rapidly progressive disease (Table 3).
4
Listing was recommended when advanced symptoms persist despite the addition of combination therapy with prostanoids, or when there are high risk features.Since the 2014 ISHLT consensus document, significant advances have occurred in risk stratification of PAH.