Frailty in lung transplantation: a narrative review of evaluation, optimization, and outcomes

Introduction

Background

Lung transplant (LTx) has become a viable treatment option for individuals who would have been historically considered too high risk to safely undergo the rigors of transplant. This includes an aging cohort of candidates, as 38% of LTx recipients are now aged 65 years and older (1) compared to 4% in 2000. These clinical practice changes have been informed by a growing amount of research in understanding and characterizing the role of age in transplant outcomes, and an evolving understanding that chronologic age is not necessarily associated with physiologic age.

Frailty is a state of increased vulnerability to stressors that can deplete physiologic reserve and increase the risk of adverse health outcomes (2,3). Compared to non-frail individuals, community-dwelling frail individuals are more likely to die, fall, be hospitalized, and become disabled, highlighting the risk of frailty within the general population (4). The two paradigms through which frailty is conceptualized are as (I) a physiologic syndrome (3) and (II) a state of accumulated health deficits (5). The physiologic syndrome identifies five core features of frailty: exhaustion, weakness, slowness, physical inactivity, and weight loss. The framework of deficit accumulation conceptualizes frailty as an index of several factors, including co-morbidities, disability, cognitive impairments, physical limitations, nutritional deficiencies, and aberrations in laboratory values. Frailty can then be quantified based on the proportion of deficits present as a function of all factors considered (2,5,6).

Pathobiologically, frailty is related to, but not synonymous with, the aging process. As patients age, their physical reserves begin to attenuate, and they acquire more health deficits; frailty represents an acceleration of this process. A combination of genetic, epigenetic, and environmental factors contribute to damage at the molecular and cellular levels, including cellular senescence, mitochondrial dysfunction, and telomere attrition (7,8). This, coupled with risk factors like inactivity and malnutrition, yield pathobiologic changes like chronic inflammation (as evidenced by increases in inflammatory markers like interleukin-6, tumor necrosis factor receptor 1, and insulin-like growth factor), sarcopenia, and immune system dysregulation. The concept of “inflammaging”, or inflammation as a component of cellular senescence, is directly linked to physical frailty (9). Once a patient is frail, subsequent stressors feed back into biological derangements, potentially accelerating frailty and decreasing the patient’s capacity to recover from events. Taken together, these patients are predisposed to falls, delirium, disability, and increased mortality (8,10).

Rationale, knowledge gap, and objective

Frailty is one potential proxy for physiologic age; as such, there is heightened interest in understanding how frailty plays a role in LTx candidate selection, management, and outcomes. Although leading societies in surgery, anesthesiology, and lung transplantation generally agree that frailty should be assessed pre-operatively and incorporated into a patient’s candidacy evaluation (11-14), there is no consensus on the most effective approach. This is due in large part to the heterogeneity of available tools for assessing frailty and the variability in how (and whether) those tools have been studied in the LTx population specifically. Most of the available literature is at the single-center level, and while some prospective and multi-center trials exist (15), a synthesis of the existing evidence and summary of knowledge gaps is lacking. Similarly, a concise overview of the potential opportunities for pre-transplant intervention on frailty is necessary to guide surgeons and pulmonologists on candidate selection and optimization. The objective of this narrative review is to discuss frailty in LTx, with a specific focus on assessment, peri-operative management, post-operative outcomes, and specific surgical considerations in the frail LTx candidate. We present this article in accordance with the Narrative Review reporting checklist (available at https://ccts.amegroups.com/article/view/10.21037/ccts-2026-1-0003/rc).

Methods

This review summarizes the current evidence regarding frailty in adult LTx candidates, with a focus on definitions, assessment tools, biological underpinnings, and clinical implications across the LTx continuum.

Literature search

A comprehensive literature search was performed using PubMed/MEDLINE and National Institutes of Health (NIH)/National Library of Medicine (NLM) to identify relevant studies published in English through December 2025. Search terms included combinations of keywords and controlled vocabulary related to lung transplantation and frailty, including “lung transplantation, lung transplant candidate, end-stage lung disease, frailty, frailty index, sarcopenia, and physical function”. Searches were limited to human studies and adult populations (≥18 years). The literature search strategy is outlined in Table 1.

Two authors (J.B.K. and J.B.S.) independently screened the titles and abstracts for inclusion (see below) and reviewed the full texts of the manuscripts included in the review. In addition, the reference lists of relevant original studies and review articles were manually reviewed to identify additional publications of interest.

Study selection

Manuscripts were considered eligible if they addressed frailty or frailty-related constructs in surgical candidates in general and in LTx candidates or recipients in particular. Eligible studies included those that:

• Evaluated frailty using established or proposed assessment tools;
• Examined associations between frailty and clinical outcomes, including waitlist mortality, delisting, perioperative complications, post-transplant survival, or functional recovery; or
• Explored mechanisms or conceptual frameworks relevant to frailty in end-stage lung disease.

Observational cohort studies, registry-based analyses, clinical trials, and systematic reviews were included. Case reports, conference abstracts, editorials, and studies focused exclusively on pediatric populations or non-lung solid organ transplantation were excluded unless findings were directly applicable to adult LTx candidates. Priority was given to studies published within the last 10 years, but relevant articles from January 1, 2000 to December 2025 were reviewed. Studies from prior to 2000 were included if and when they appeared in the references of other texts, added substantial relevance, and otherwise met inclusion criteria.

Data extraction and synthesis

Data was extracted qualitatively from included studies, with attention to study design, patient population, timing and method of frailty assessment, and reported associations with clinical outcomes. Given the heterogeneity of frailty definitions, measurement instruments, and outcome reporting across studies, quantitative pooling of results was not performed.

The literature was synthesized thematically, emphasizing:

• Conceptual models of frailty relevant to end-stage lung disease;
• Commonly used frailty assessment tools and their applicability to LTx candidates;
• Prevalence and longitudinal changes in frailty before and after transplantation;
• Associations between frailty and waitlist, perioperative, and post-transplant outcomes; and
• Emerging evidence supporting frailty as a potentially modifiable risk factor.

This review was conducted in accordance with previously described methodological guidance for narrative reviews (16). Efforts were made to provide a transparent and balanced synthesis of the available evidence, with particular attention to areas of consensus, controversy, and knowledge gaps relevant to clinical practice and future research in lung transplantation.

Frailty and surgical outcomes

As the population ages, surgeons and anesthesiologists will encounter more frail patients in the pre-operative period. The prevalence of frailty within the surgical population varies by age, procedure, and frailty assessment used, but the range is estimated to be between 7% and 40% (17-20). Independent of surgical procedure performed, pre-operative frailty is associated with an increase in hospital length of stay, risk of non-home discharge, and rate of post-operative adverse outcomes (20-23).

Recognizing the increased physiologic stress that surgical procedures impose upon frail patients and the risk of deleterious post-operative outcomes, myriad surgical, geriatric, and anesthesia societies recommend pre-operative screening of older adults for frailty or cognitive impairment (11-13). Despite these recommendations, adoption of pre-operative frailty screening has been slow, likely due in part to the multitude of screening instruments. A recent systematic review and meta-analysis by Aucoin et al. (24) compared various frailty screening tools in terms of (I) their accuracy in predicting post-operative mortality and (II) feasibility of implementation. In this review, the Clinical Frailty Scale (CFS) was found to have the greatest effect size for predicting post-operative mortality [odds ratio (OR) =4.89], although the Fried frailty phenotype (FFP) was the most commonly used and also strongly predicted post-operative mortality (OR =3.79) (24). There may also be a role for utilizing automated, electronic health record-based screening indices, which also effectively demonstrate an association between pre-operative frailty and higher post-operative mortality, readmission rates, and the need for post-acute care (25).

Frailty, pulmonary disease, and lung transplantation

Even before patients with chronic lung disease progress to meeting criteria for lung transplantation, they are at increased risk of frailty. Systematic reviews estimate the prevalence of frailty in chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) at around 19% and 12–55%, respectively (26,27). There are a variety of social, physiologic, and environmental factors related to chronic lung disease that may predispose these patients to the eventual development of frailty, including anxiety related to pulmonary symptoms, smoking, physical inactivity, nutritional deficiencies, and multimorbidity. Additionally, frail patients with lung disease may be at an increased risk of exacerbations and more prone to disability and death following exacerbations (8). Frailty is also associated with increased mortality, hospital admissions, and reduced quality of life in these patients (28,29).

As LTx is one therapeutic option for select patients with end-stage lung disease, there has been a surge in interest in better understanding the implications and potential management of frailty specifically in LTx. Frailty is a common syndrome in LTx candidates, with a recent review estimating its prevalence between 10% and 45% in LTx candidates (7). Frail LTx candidates are weaker and have poorer waitlist outcomes than non-frail candidates. A single-center, cross-sectional study of adults with chronic lung disease undergoing evaluation for LTx found that, even after adjusting for age, gender, underlying pulmonary diagnosis, and lung allocation score, frailty is associated with significantly reduced exercise capacity on cardiopulmonary exercise testing prior to transplant (30). Once patients are listed, frailer transplant candidates not only have higher levels of disability, but they also have higher 1-year incidence of death or de-listing than non-frail patients (27–36% versus 13–16%) (9), and a significantly higher waitlist mortality (31,32). Additional research is needed to better characterize how frailty changes over time while awaiting transplant following listing and whether those trends have implications for post-operative recovery and mortality.

Most experts agree that pre-transplant frailty is associated with increased post-transplant mortality, although data is less consistent. When Kim et al. (33) explored the relationship on a national level across over 15,000 LTx recipients, frailty was associated with higher odds of in-hospital mortality and non-home discharge following lung transplantation. Singer et al. (15) performed one of the few multi-institutional prospective studies in this space, and they found that pre-operative frailty was associated with an increased one-year mortality following LTx, a relationship that was preserved across two different frailty assessment tools [Fried frailty phenotype (FFP) and Short Physical Performance Battery (SPPB)]. The same association was replicated across multiple single-center studies that utilized frailty deficit indices to assess pre-transplant frailty (34-36). In contrast, a few single-center cohort studies did not demonstrate a significant association between pre-transplant frailty and post-transplant survival (32,37,38). Some of the heterogeneity may be due to the instruments used to predict frailty as well as institution-specific practices, given that the studies that have not demonstrated a clear relationship have largely been single-institution.

Frailty instruments

Given that frailty is a risk factor for deleterious outcomes in patients with chronic lung disease, surgical patients, and LTx candidates, the International Society for Heart and Lung Transplantation (ISHLT) recommends screening for frailty as part of a patient’s full initial evaluation for LTx candidacy (14). There are a multitude of tests utilized both clinically and in research to characterize frailty, most of which are based on either the “phenotype” or the “deficit accumulation” model of frailty summarized in Table 2, and most of which were developed and validated in the general geriatric population. The tests include both laboratory values extracted from the medical record as well as functional testing and patient reported measures.

Despite the ISHLT’s recent recommendation to incorporate frailty screening into patient assessments and similar such guidelines across other organizations, the optimal frailty instrument is not yet known (44,45). The existing instruments capture a variety of factors, and a recent study by Swaminathan and colleagues (46) demonstrated that the correlation between a subset of measures is overall poor. Specifically, they found that while SPPB and frailty index (FI) were both independently associated with decreased 1-year post-transplant survival, there was no significant correlation between SPPB and FI themselves.

Given the unique characteristics of the LTx candidate patient population, it is plausible that a tool validated for the general geriatric population may not be optimal for LTx candidates. Singer et al. (44) sought to fill this gap by developing the Lung Transplant Frailty Scale (LT-FS; Table 2), which is a disease-specific frailty measure validated in LTx candidates. The LT-FS combines measures of strength and mobility from the FFP and SBBP with measures of inflammation, and the three resulting LT-FS models of frailty assessment were more strongly associated with de-listing or death in LTx candidates than both the FFP and the SPPB alone. Pre-LTx frailty by LT-FS was also associated with post-transplant mortality; the same association was not identified when the FFP or SBBP alone were utilized to assess pre-LTx frailty (44). The ISHLT is developing an updated consensus statement about frailty in LTx candidates, which may offer recommendations about frailty instrument selection.

Can frailty be reversed pre-transplant?

Given the clear association between frailty in LTx candidates and worse pre-transplant outcomes (i.e., de-listing, death), transplant centers are keenly interested in mitigating risk. While certain aspects of frailty in this population are innately tied to immutable biological factors and/or the underlying disease process, other factors are potentially modifiable, including physical activity and nutrition. Walsh et al. (47) prospectively assessed patients undergoing LTx evaluation using a wearable device and found that extremely sedentary patients were significantly more likely to die prior to transplantation, findings which were replicated by Komatsu et al. (48) using a self-reported nutrition instrument. Pre-transplant physical activity is also associated with post-transplant survival (49).

The mainstay of pre-transplant physical activity optimization is enrollment in pulmonary rehabilitation (PR). Participation in PR programs unequivocally improves important outcomes in chronic respiratory disease, including increasing exercise capacity, improving healthcare-related quality of life, reducing dyspnea, and reducing post-hospitalization mortality in patients with COPD (50). However, its impact on outcomes for LTx candidates is less understood. One systematic literature review of PR in LTx candidates by Hoffman et al. (51) noted a lack of consistent evidence in this space, identifying only six studies assessing the impact of PR during the pre-LTx period. Most of the studies found an increase in quality of life and six-minute walk distance (6MWD) following completion of the PR program; however, outcomes such as impact on frailty, mortality, and de-listing were not described (51).

A more recent systematic review by McGarrigle et al. (52) explored the impact of pre-transplant rehabilitation on frailty specifically. They identified 15 studies describing the impact of a wide variety of interventions (PR, strength programs, exercise programs) and settings (in-person individual and group, app-based, home-based) on a heterogeneous group of frailty-related outcomes (frailty phenotype, SPPB, gait, strength). The studies that assessed the impact of rehabilitation programs on frailty phenotype and SPPB did show a reduction in frailty after completion of the programs. However, the authors’ conclusion was that the evidence is low-certainty and relatively low-quality, and further research is needed (52). Regardless, PR remains a core aspect of most LTx programs because (I) 6MWD is predictive of waitlist outcomes (53) and (II) PR programs facilitate LTx candidates’ maintenance of pre-LTx exercise capacity (54,55). It follows logically that enrollment in PR may address frailty and/or facilitate positive pre-transplant outcomes, although more research is needed in this area. It is also important to acknowledge that not all patients with end-stage lung disease have access to a formal PR program, which may limit the feasibility of enrollment of all LTx candidates.

Another potentially modifiable factor that is of interest to transplant programs is patient nutrition. Recognizing the complex pathobiological underpinnings of frailty, nutrition status is incorporated into many of the commonly used frailty instruments, including the FFP, CFS, and FI, among others (Table 2). It follows that improving nutritional status may decrease frailty, and nutritional supplementation has been conditionally recommended as a potential intervention to target frailty (2,56). Racey et al. (57) published a systematic review and meta-analysis of the impact of nutrition interventions on frailty, and they found that interventions including oral nutrition supplements and fortified/enhanced foods significantly reduced frailty and improved physical function and mobility. Although the effect size was relatively small and the long-term impacts were not analyzed, nutrition interventions may hold promise in the pre-transplant context.

Although it is not synonymous with frailty, it is worth noting that sarcopenia, characterized by loss of skeletal muscle mass and function, is increasingly recognized as a significant factor influencing outcomes in LTx recipients. Sarcopenia is common in LTx candidates (58), and studies using imaging-based measures of skeletal muscle mass and composition demonstrate that pre-operative sarcopenia is associated with poorer short-term outcomes after lung transplantation, including a higher rate of postoperative tracheostomy, increased operative mortality, prolonged mechanical ventilation, and longer intensive care stays (59). Additionally, in older LTx candidates, sarcopenia correlates with longer post-transplant hospital stays and may contribute to frailty, which itself is linked to adverse outcomes (60). While some cohorts have not shown a direct effect of thoracic muscle sarcopenia on long-term survival (61), the broader literature suggests that low muscle mass and poor muscle quality are predictors of complications and may increase mortality risk in solid-organ transplant populations, including lung recipients (62,63). Importantly, longitudinal data indicate that physical function and muscle mass can improve after transplant, with sarcopenic individuals demonstrating recovery toward non-sarcopenic levels over time, underlining the potential for rehabilitation interventions to mitigate some adverse effects (64,65).

Can frailty be reversed post-transplant?

Given the extent of the surgery and the associated recovery process, an understanding of post-LTx frailty is important to ensure optimal recovery. Wickerson et al. (66) systematically reviewed the literature studying post-LTx exercise training programs and described an association between structured training and exercise capacity and strength. A similar relationship seems to exist between post-LTx exercise programs and frailty: when patients underwent targeted physical therapy or exercise programs after LTx, over 80% of patients who were frail prior to transplant had resolution of frailty by month 6 post-transplant (67) and month 12 (68).

It is worth noting that some component of this improvement in frailty may be attributable to the transplant itself. One prospective study by Venado et al. (69) followed 246 patients who underwent LTx and found that 84% of previously frail patients were no longer frail 6 months following LTx based on improvements in SPPB and FFP; and after this time period there was no significant improvement in frailty scores. Patients who were not frail prior to transplant generally maintained stable scores on their frailty assessments following transplantation. Although many of these patients undoubtedly underwent some sort of post-transplant exercise program, this was not described as an intervention, and Venado et al. postulate that their findings are likely related to an improvement in the pathobiological processes that contribute to frailty post-transplantation (69).

Additional surgical considerations

Even beyond the question of general candidacy for a LTx, teams are faced with additional questions for their patients with chronic lung disease that may have implications for patient frailty—namely, whether a patient requires extra-corporeal membrane oxygenation (ECMO) during the course of their care and whether they are offered a single or bilateral LTx (SLT or BLT, respectively).

ECMO is typically utilized in one of two contexts in the pre-LTx setting: (I) as a ECMO-bridge to transplantation (ECMO-BTT) or (II) in the context of acute respiratory failure prompting inpatient evaluation for transplant. Trindade et al. (70) recently surveyed international transplant centers to describe their ECMO-BTT practices. Of the 69 centers who responded, nearly every center (93%) performs at least one ECMO-BTT case per year, with nearly half (43%) performing six or more. Notably, nearly all responding centers (90%) have no written protocol for ECMO-BTT at their institution, highlighting the critical importance of understanding the risk factors associated with this practice.

It is broadly understood that frailty is associated with increased risk of mortality in intensive care unit (ICU) patients as well as in those receiving mechanical ventilation (71,72), but the association between frailty and outcomes following ECMO has not been well-described. One recent registry review comprising 2084 ECMO patients found a 12.2% prevalence of frailty by the CFS, but there was no difference in adjusted 1-year mortality between frail and non-frail ECMO recipients (73). A clear association between increased age and mortality in ECMO recipients has been described (74,75), but most of these studies excluded ECMO-BTT patients, and age is certainly not synonymous with frailty. Further research is needed to better characterize the risk factors for poor post-ECMO outcomes to better determine how to allocate this resource in the LTx candidate population.

Another surgical consideration is whether a patient may benefit more from a SLT or BLT. Although the literature suggests a long-term survival benefit associated with BLT (76,77), surgical time and post-operative ICU and hospital days are shorter in SLT (77). As a result, there is an ongoing debate about the ongoing role of SLT, with data interpretation confounded by the selection bias that is inherent in the choice to offer a single versus bilateral transplant (78,79). Specifically, there remains the possibility of equipoise in older patients (78,80), which raises the question of whether pre-transplant frailty should inform type of transplant offered. While age is certainly different from frailty, frailty prevalence does increase with age, so it is plausible that some of the age-related effects are driven by frailty. Indeed, although the relationship between SLT/BLT and frailty has not been directly studied, a number of the seminal studies in the LTx and frailty space either acknowledge or explicitly control for transplant type in their models (15,36), suggesting that this is an area of further research need.

Study limitations and future directions

Limitations to the studies and data reviewed include the single-center and/or retrospective nature of many of the studies, which can limit applicability to the broader transplant population. Many LTx centers have unique protocols regarding pre-operative evaluation, candidate selection, surgical techniques, and post-operative management (e.g., immunosuppression and prophylaxis management, frequency of follow-up, post-operative rehabilitation) that may lead to variability in outcomes from one center to another. Additionally, many of these studies span various eras in transplantation, during which medical and surgical advances may have played a role in transplant outcomes that cannot necessarily be controlled for. Furthermore, none of the frailty tools other than the LT-FS were originally developed in LTx candidates, so their applicability and ability to predict relevant outcomes remains an area of ongoing interest. Evidence-based society guidelines would be of significant benefit in this space as currently there is not universally accepted method amongst transplant centers for assessing and monitoring frailty.

Areas for future research include identifying the optimal assessment tool, which in part may enable more consistency between centers to promote collaboration, optimization of pre-operative management of frailty, more accurate identification of patients who are likely to recover from frailty post-operatively, and optimization of surgical techniques with regard to bilateral versus single LTx, or implementation of minimally invasive LTx to reduce post-operative recovery time. Of additional interest would be understanding if frailty is a significant factor in managing patients who decompensate and require mechanical circulatory support as a bridge to transplant or bridge to decision.

Conclusions

Lung transplantation represents the only curative, life-prolonging intervention for individuals living with chronic end-stage lung disease. However, it is a limited resource and a high-risk surgical procedure, so LTx programs have a responsibility to identify and address co-morbidities that place individuals at risk for complications. Frailty is one such major co-morbidity with unique applicability for risk stratification of LTx candidates given its independent association with both chronic pulmonary disease and poor surgical outcomes. Although the existing literature on frailty and LTx is relatively heterogeneous, there is a strong signal that pre-transplant frailty is a risk factor for waitlist death, de-listing, and decreased post-transplant survival. The LTx community has a responsibility, therefore, to identify the optimal frailty assessment tool and to ensure its more uniform application. Once identified, frailty can likely be mitigated to an extent by pre-transplant PR and nutritional support, with the long-term goals of optimizing patients’ eligibility for transplantation and improving post-transplant outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://ccts.amegroups.com/article/view/10.21037/ccts-2026-1-0003/rc

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-2026-1-0003/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-2026-1-0003/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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