Deconditioning or biology? Triaging frailty in lung transplant candidates

Extract

The essential question in evaluating lung transplant candidates is whether that individual will benefit from transplantation. While lung transplantation is associated with improvements in physical function, quality of life, and survival for appropriate candidates, inappropriate selection is not only harmful to the candidate but to others on the waitlist. Understanding who stands to benefit from lung transplantation requires comprehensive assessment of potential risk factors. Some of these risk factors, such as age, organ dysfunction, or malignancy, cannot be reversed. Addressing modifiable risk factors, such as obesity, malnutrition, coronary artery disease, infections, or gastro-oesophageal reflux disease can allow otherwise marginal candidates to succeed [1].

Shareable abstract

Frailty in lung transplant recipients is a complex multidimensional process. In-depth understanding of biological mechanisms in frail candidates is needed to adopt a tailored approach and maximise clinical benefit. https://bit.ly/4bSobvX

The essential question in evaluating lung transplant candidates is whether that individual will benefit from transplantation. While lung transplantation is associated with improvements in physical function, quality of life, and survival for appropriate candidates, inappropriate selection is not only harmful to the candidate but to others on the waitlist. Understanding who stands to benefit from lung transplantation requires comprehensive assessment of potential risk factors. Some of these risk factors, such as age, organ dysfunction, or malignancy, cannot be reversed. Addressing modifiable risk factors, such as obesity, malnutrition, coronary artery disease, infections, or gastro-oesophageal reflux disease can allow otherwise marginal candidates to succeed [1].

Frailty is a potentially modifiable risk factor that is highly prevalent among lung transplant candidates. Conceptually, frailty encompasses age-associated traits such as slowness, wasting, sarcopenia (low muscle mass), imbalance, decreased activity, exhaustion, adiposity, systemic inflammation, and anaemia [2]. Frailty is associated with delisting and death on the transplant waitlist [3], as well as poor health-related quality of life and mortality after transplant [4]. Generally, frailty is addressed through structured exercise and nutrition programmes [5].

A complicating issue is that frailty has been differently defined across studies, ranging from a focus on a single physiological trait to a holistic integration of multiple health-associated parameters [6]. Narrowly, sarcopenia alone can predict waitlist outcomes [7]. The Short Physical Performance Battery (SPPB), a physical function-focused frailty metric incorporating speed, strength, and balance, performs well in lung transplant settings [8, 9]. More broadly, the Fried Physical Frailty Phenotype quantifies shrinking, weakness, speed, and physical activity. However, a lung-transplant specific frailty scale, including balance, grip, gait, and systemic inflammation, outperforms these more generic measures for the prediction of waitlist delisting or death [2]. Increasingly broad metrics can capture additional frailty-associated concepts beyond physical functioning domains, including neuro-cognitive or social deficits. A cumulative deficits index, counting the number of co-morbidities, is a simple and potentially useful tool [10]. Rockwood's Clinical Frailty Scale (CFS) is another broad frailty metric, which quantifies the progression from exceptionally fit (score of 1) through decreasing activity and then increasing dependency to terminally ill (score of 9) [11].

In this issue of ERJ Open Research, Kuhnert et al. [12] examined the CFS in a cohort of lung transplant recipients with interstitial lung disease (ILD). In this single-centre cohort study, frailty was assessed by CFS pre-transplant, 4-months post-transplant, and then 5-years after transplant. The CFS scores decreased (meaning frailty improved) in 93% of recipients, with the greatest improvements in those who were most frail pre-transplant. These findings align with data from a University of California, San Francisco cohort showing improvements in frailty following lung transplantation as measured by SPPB [4]. Further, improvements in the Lung Transplant Valued Life Activities metric were associated with improved quality of life and chronic lung allograft dysfunction (CLAD)-free survival [13], while incipient frailty (decreasing SPPB) predicted CLAD risk [14]. Consistent with these trajectory data, Kuhnert et al. [12] found that decreases in CFS (implying less frailty) were associated with reduced mortality risk. Some individuals developed worsened frailty according to CFS, particularly following prolonged intensive care unit stays. The 7% of recipients for whom frailty worsened experienced very poor outcomes, with a <2-year post-transplant survival.

Triaging individuals whose frailty will resolve with transplantation, those who could respond to prehabilitation, and those who will have poor outcomes despite interventions is the central issue. It is important to note that the standard protocol for this study was essentially a high-intensity frailty intervention that is not universally practiced. Candidates underwent endurance and resistance training and nutritional support, while post-transplant care focused on early mobilisation, structured rehabilitation and weight control. One interpretation of these findings is that some individuals will remain susceptible to frailty-related complications despite universal prehabilitation.

Frailty in individuals with ILD may be driven by pulmonary or extrapulmonary features (figure 1). Understanding the biology of frailty may help unravel the limitations of exercise-based frailty interventions [15]. Whether frailty reflects deconditioning and physiological limitations from end-stage lung disease versus some underlying biological process may determine who stands to benefit. While we tend to associate the biological drivers of frailty with narrow clinical phenotypes, such as sarcopenia, discrete biological changes can lead to surprisingly diverse clinical deficits. For example, heterotopic transplant of elderly hearts to younger mice resulted in impaired grip strength, walk distance, and augmented anxiety through senescent-cell derived mitochondrial DNA [16]. Frailty in these mice could be reversed with medications that target senescent cells, but senescent cells vary in their susceptibility to apoptosis [17]. Lung transplant candidates with ILD are frequently found to have short telomere syndrome, and telomere dysfunction directly leads to cell senescence through the activation of DNA damage pathways. Interestingly, we have seen that telomere dysfunction is associated with worse frailty in transplant recipients with ILD [18]. Telomere dysfunction-associated senescent cells may persist following transplantation if telomere dysfunction is systemic. Senescence drivers related to the dysfunctional lung could be directly addressed through lung transplantation. Chronic hypoxia in end-stage lung diseases and anaerobic metabolism can drive muscle wasting and sarcopenia [19]. Additionally, fibrotic lung tissue could directly lead to frailty. For example, matricryptins are extracellular matrix fragments that participate in pathogenesis of fibrosis through fibroblast activation and differentiation [20, 21]. Transplantation might remove the local source of matricryptins thereby interrupting a driver of frailty. Future research may reveal whether persistent extra-pulmonary drivers of frailty impair post-transplant recovery.

FIGURE 1.

Pulmonary and extra-pulmonary drivers of frailty. Frailty in individuals with advanced interstitial lung disease may have lung-centric or systemic drivers. Mitochondrial DNA, reactive oxygen species, extracellular matrix components (matricryptins), or senescent cells may be released from the diseased lung or other tissues. Biological drivers of frailty that remain after transplant may contribute to progressive dependence and disability, as measured in the Clinical Frailty Scale. Figure partially created with BioRender.com.

Frail lung transplant candidates present both challenges and opportunities. With thoughtful clinical protocols, many frail candidates could benefit tremendously from transplant. For the rest, unpacking the biological drivers of frailty may lead to targeted therapies or at least calibrated expectations.