Introduction

In medicine, we are accustomed to discussing the risks and benefits of medical interventions. In the field of lung transplantation, this is no different. Each year, more than 2500 patients in the USA undergo lung transplantation, and prior to the decision for the patient to proceed with this potentially life-saving intervention, there is a significant evaluation process and analysis of the risks and benefits [1]. The stakes however are much higher than for many other procedures. Patients, members of the interprofessional transplant teams, regulating agencies, and members of the public may all have different priorities when assessing the risks, benefits, and outcomes, making the determination of which candidates meet the criteria for listing even more complicated. From the patient’s perspective, a lung transplant often is considered a life and death decision—as such, the patient is often willing to assume risks far greater than may be acceptable for other surgical procedures. Yet, unlike other procedures, where the decision to proceed despite substantial risk may primarily impact only the patient and their loved ones, the decision to proceed with a lung transplant for one patient has the potential to negatively impact the outcomes for other patients who are awaiting the same procedure. Thus, the risk–benefit analysis to determine whether to list a patient for lung transplant must draw upon the ethical principles of not only autonomy, but also utility, justice, and efficiency [2].

Consequently, the assessment of patient-specific risk factors is essential when evaluating a patient for a lung transplant. Particularly challenging is that many of these patient-specific risk factors require subjective and qualitative assessment. The research to study these risk factors is difficult and, when conducted, often limited. This paper aims to review our current understanding of the estimation of patient-specific risk factors.

Referral and Evaluation of Candidates for Lung Transplant

The process of evaluation and determination as to whether an individual shall be listed as a candidate for lung transplant frequently is referred to as “candidate selection”—however, it should not be viewed as if one individual is selected and determined to be better than other candidates, but rather a comprehensive assessment to identify individual risk factors, calculation of estimated risk considering the identified risk factors, and a determination of whether that patient’s risk profile is one that is acceptable to the transplant center while considering the center’s tolerance for risk and expertise. Early referral is strongly encouraged to provide sufficient time for this evaluation and then optimization to reduce risk whenever possible.

Evaluation of a candidate for a lung transplant can be divided into disease-specific factors and patient-specific factors. Disease-specific factors primarily relate to when a patient with a disease with an indication for a lung transplant has progressed to a stage in the disease course to warrant consideration of a lung transplant as a therapeutic option—specifically when a patient should be considered for (1) referral and (2) listing. The tables in the ISHLT consensus document pertaining to lung transplant candidates outline disease-specific factors with criteria for referral and listing [3••].

Patient-specific factors primarily relate to an individual’s overall condition, including their comorbid conditions, their insight into their disease, and their ability to manage a complex medical regimen following the surgical procedure. It is the identification of these risk factors and estimation of risk for adverse outcomes that become essential in determining whether an individual is a candidate for a lung transplant. It is the assessment of these risk factors that require detailed evaluation and testing to determine which patient-specific attributes might contribute to the ultimate outcome in both the short- and long-term after lung transplant. There are a few situations where these patient-specific risk factors should be considered contraindications (see Table 1); however, many are modifiable, and most need to be considered together as accumulated risk factors, placing the candidate at increasing risk for an adverse outcome [3••].

Table 1 Patient-specific risk factors considered contraindications to lung transplant [3••]
Full size table

Patient-Specific Risk Factors

In the determination of patient-specific risk factors, we are guided primarily by expert opinion and consensus documents [3, 4, 5]. In addition to these documents, the published literature is limited. For most identified risk factors, there are only retrospective reviews and case series publications. For the few areas where there are prospective research studies, much of the data continues to be hampered by the selection bias inherent in who is referred for lung transplant and who is listed at each center.

This review is not exhaustive of the potential risk factors that might be identified during the evaluation. Other risk factors such as chest wall or mediastinal abnormalities or alloimmunization may also be factored into the calculation of risk. Table 2 categorizes the lung transplant patient-specific risk factors identified in the 2021 ISHLT consensus document into high and average risk, noting that risk may increase substantially when more than one risk factor is present [3••]. Candidates for a lung transplant are considered individually, and each center may have identified areas of expertise and different risk tolerance related to multifactorial pressures. Thus, it is essential for each transplant center to clearly communicate to candidates which patient-specific risk factors have been identified and how these impact their candidacy.

Table 2 Table of risk—lung transplant candidate patient-specific risk factors [3••]
Full size table

Nutritional Status and Body Mass Index

Nutritional status should be assessed in all lung transplant candidates, with markers such as prealbumin, albumin, weight, and body composition used to evaluate each individual [6]. Low albumin (< 3.5) and low prealbumin levels (< 18 g/dL) have been associated with worse outcomes [7]. While body mass index (BMI) alone may not be the most accurate assessment of nutritional status, both BMI < 17 kg/m2 and > 35 kg/m2 prior to lung transplant have been associated with worse outcomes [8]. Patients who are obese are at increased risk for perioperative complications including primary graft dysfunction as well as decreased survival [9]. Since candidates present with a wide variety of nutritional states, individualized nutritional support plans are instrumental in mitigating these risks. Patients who are underweight with a low BMI or presenting in a malnourished state may need not only caloric support (and possibly a feeding tube) but often optimization of their oxygen delivery and sometimes pharmacologic interventions to stimulate appetite. Similarly, those who are overweight benefit from weight loss, ideally in coordination with an exercise program aimed at preventing the loss of muscle mass.

Frailty

The concept of physical frailty as a condition of reduced function and health has been the focus of considerable research over the past decade [10,11,12]. When present in pretransplant candidates, frailty has been associated with an increase in post-lung transplant mortality [11]. Although it has emerged as a strong patient-specific risk factor for poor outcomes after lung transplant, it has also been shown to be a modifiable or reversible risk factor [13,14,15,16,17].

Despite the ongoing research, the optimal assessment of frailty in lung transplant patients has yet to be defined. Recently, a novel “lung transplant frailty scale” has been developed with improved predictive validity in lung transplant patients [18••]. This lung transplant-specific frailty scale (https://lungtransplantfrailtyscale.ucsf.edu/) which incorporates physical measurements (including balance, grip strength, gait speed) and biomarkers, once validated in other lung transplant cohorts, has the potential to be incorporated into clinical decision-making in the assessment of lung transplant candidates.

Comorbidities/Extrapulmonary Organ Dysfunction

Ideally, candidates for a lung transplant have single-organ dysfunction. Often, however, this is not the case, which can impose risks on both patient and allograft survival. The presence and severity of comorbidities such as coronary artery disease, heart failure, peripheral vascular disease, and cerebrovascular disease need to be evaluated carefully, as they have the potential to impact perioperative complications and overall survival [3••]. Liver and kidney diseases also need to be carefully assessed, especially considering not only the disease itself but also the potential to impact post-transplant medication regimens due to their metabolism and toxicities [19, 20]. Similarly, hematologic abnormalities can create challenges including bleeding and clotting risks or limit optimal maintenance immunosuppression. Bone marrow biopsy may be indicated in candidates at risk for hematologic abnormalities, such as telomere gene mutations, to fully understand the risk and to trial therapeutic intervention [21]. Comorbid conditions must be optimized; however, when multiple are present, the risk may be too great to proceed with a lung transplant.

Infections

Uncontrolled infection can pose a significant risk for a patient who will require immunosuppression following a lung transplant. Advances in therapeutic interventions have now made very few infections absolute contraindications to a lung transplant. Patients with viral pathogens that were previously considered barriers such as hepatitis C and human immunodeficiency virus have been shown to have acceptable short- and long-term survival post-lung transplant when viral loads are undetectable prior to transplant [22, 23].

A few multidrug-resistant organisms remain (including Mycobacteria abscessus and Burkholderia cepacia complex) which do require specialized expertise and management protocols to achieve satisfactory post-lung transplant outcomes [24,25,26]. Thus, lung transplant candidates with one of these infections may need to be referred to a transplant center that considers this patient-specific risk factor to be modifiable or at an acceptable level of risk.

Malignancy

A comprehensive history and screening for malignancy are essential when a patient is being considered as a candidate for a lung transplant, especially since recipients require lifelong immunosuppression following transplant. Each patient with a history of prior cancer or found to have cancer during the evaluation process needs to be considered individually and in coordination with an oncologist with expertise in the specific cancer. The estimation of the risk of the cancer will be guided by the type of cancer, the time since the cancer treatment was completed, the natural history of the cancer with its risk of recurrence, and the likelihood of response if additional therapy is required following transplant [27]. Each type of cancer carries its own risk profile. Some types of cancer (including completely treated ductal carcinoma in situ or stage 1 breast cancer, treated early-stage endometrial or cervical cancer, resected early-stage renal cell carcinoma, and low-risk prostate cancer) may not pose a substantial risk, even without waiting any significant time interval prior to transplant. In contrast, other advanced cancers are considered to carry such a high or prohibitive risk that solid organ transplantation may not be a recommended option even more than 5 years after the cancer diagnosis. Consensus documents created by the American Society of Transplantation provide detailed recommendations about the timing of listing for some of the most common solid and hematological malignancies [27, 28].

Cognitive and Psychologic Factors Including Insight into Medical Condition and Health-Related Behaviors

Lung transplant requires not only that a patient undergo a major surgical procedure, but also adhere to a complex medical regimen of lifelong immunosuppression and ongoing monitoring of their medical condition. Therefore, the candidate must be able to understand their underlying diagnosis, to know when to communicate with the health care team and seek medical attention, to follow medical advice, and to realize the implications of changes in medications that might impact the immunosuppression regimen. Cognitive impairment, psychological distress, and substance use disorders have the potential to impair an individual’s ability to manage the complexities of the medical regimen following a lung transplant. A detailed history, as well as a neurocognitive and psychological assessment, is required to identify and determine a plan for mitigation of these risk factors [3, 29, 30].

Optimization of mental health is strongly recommended prior to lung transplant, as depression and anxiety are risk factors for morbidity and mortality following transplant [31]. Screening, and therapeutic intervention when detected, should be considered for all individuals undergoing evaluation for a lung transplant.

Substance use (including tobacco, alcohol, cannabis, and other recreational drugs) following lung transplant has been associated with non-adherence as well as other consequences such as interference with immunosuppression and injury to the transplanted lung [30]. Pretransplant substance use is strongly correlated with post-transplant use and, thus, demonstrated that abstinence and participation in 12-step programs are often required to attempt to mitigate risk [32].

Sociodemographic Factors

Undergoing a lung transplant has many associated financial costs, ranging from temporary housing and transportation to medication co-pays. Transplant centers should take steps to ensure there is no discrimination on the basis of financial resources and to ensure that potential candidates from all backgrounds have equal access to lung transplant.

Thus, transplant centers are encouraged to be proactive in their plans to identify patients who may experience financial hardships and to develop resources to mitigate the risk. In the USA, health insurance coverage is essential for meeting the medical expenses of a lung transplant. Financial coordinators can be instrumental in helping patients understand and apply for optimal insurance and pharmaceutical benefit plans. Transplant social workers and pharmacists can be helpful in identifying additional resources for housing, food, transportation, and pharmacy coverage.

Age

Older age (usually considered ≥ 65 years) often is tied to many of the risk factors described above, including physical frailty, decreased functional status, declining cognitive function, and other diagnosed or as yet undiagnosed comorbidities including atherosclerotic diseases (coronary artery disease, cerebrovascular disease, peripheral vascular disease), esophageal dysmotility, and malignancy [33]. Patients over 65 years at the time of transplant have been documented to have decreased long-term survival [34]. However, the question has been raised as to whether physiological aging (accounting for frailty, body composition, and neurocognitive and psychosocial function), rather than chronological aging, might be a better predictor for adverse outcomes following lung transplant [35]. Conversely, in addition to the risk of adverse outcomes, there is concern about the societal impact and ethical principles when considering the allocation of organs to older candidates. The “fair innings” principle is often evoked when considering if there should be an age limit or prioritization for younger recipients who have lived fewer life years [36]. Indeed, in the USA, the allocation system has taken this into consideration granting priority to those who have not had the opportunity to pass through as many life cycles (e.g., children have the highest priority) [37].

Risk Reduction

It is important to note that many of these patient-specific risk factors are modifiable. There is evidence that efforts to modify risk factors may result in improved post-lung transplant outcomes. For example, patients, who are overweight to obese and who lose weight prior to lung transplant, have a proportional increase in survival [38]. Similarly, those patients who are frail or debilitated do better if they participate in pulmonary rehabilitation or improve their physical fitness before lung transplant [9, 39]. Whether it is the weight loss and the gains in physical fitness, or the patients’ motivation to achieve these results that leads to improved outcomes, patients who are referred with sufficient time can improve their own candidacy. In addition, early referral enables the optimization of the management of other comorbidities, infections, and even mental health.

When considering patient-specific risk factors, it is essential that health disparities are neither created nor perpetuated. Analysis of registry data has suggested that access to the lung transplant waitlist is worse in non-white candidates [40]. It has been suggested that delays in referral may be contributing to some of these health disparities. Efforts should be made to encourage early referral of all patients to allow sufficient time to identify and mitigate risk, as well as to allow candidates to prepare themselves for the life-changing medical intervention they are considering.

Conclusions

Evaluation of potential candidates for a lung transplant is one of the more challenging tasks confronting a lung transplant center. The assessment of risk and the ultimate determination as to whether an individual is estimated to have too many accumulated risk factors should not be made by a single provider alone. The final assessment of an individual’s candidacy requires input from an interprofessional team because lung transplant recipients not only undergo a major surgical procedure but also must adhere to a complex regimen of lifelong immunosuppression and ongoing monitoring of their medical condition. Each potential lung transplant candidate undergoes a detailed evaluation, with the goal to ascertain a complete assessment of patient-specific risk factors. This is especially important when modifiable risk factors are identified as potential barriers to listing. With sufficient time, individuals may be able to reduce their risk of an adverse outcome and improve their candidacy. However, this too requires a risk–benefit analysis in considering whether the candidate has the time to modify the risk factor before their underlying disease progresses.

Allocation systems are updated regularly to try to improve the allocation of organs, now with most incorporating urgency, yet every year, people continue to die on the waiting list while awaiting this limited organ [37]. Thus, there is an added pressure in considering who is a suitable candidate for a lung transplant—the pressure of knowing that if lungs are allocated to someone who is not an optimal candidate, then another candidate, who perhaps has done more to optimize their candidacy or who has a better chance of long-term survival based upon their risk factor profile, may not make it to lung transplant. Thus, transplant centers must be as transparent as possible in these high-stakes calculated assessments of risks and benefits, while also taking into consideration not only the individual patient’s outcome, but also other potential candidates and greater societal priorities.