Frailty: A Strong Impact on Lung Transplant Outcomes?

Abstract

Frailty, defined as an increased risk of adverse health-related outcomes because of a maladaptive response to stress, is common among patients with advanced lung disease awaiting lung transplantation. Clinical features of frailty include weakness, decreased agility, fatigue, physical inactivity, and loss of muscle mass. Frailty has profound prognostic ramifications on lung transplant candidates, including an increased risk of waitlist mortality and decreased posttransplant survival for up to 4 y posttransplant.1,2 Pretransplant frailty is also a risk factor for sustained weakness, disability, and decreased quality of life in the posttransplant setting.3 Among patients who develop pretransplant frailty, approximately 15% to 20% have irreversible and progressive sequelae, especially in patients with sarcopenia (as measured by hand-grip strength), extremes of body mass index, malnutrition (albumin), and renal dysfunction.3,4 Although our understanding of frailty in the post–lung transplant setting has vastly improved over the past several years, there is still much to learn regarding the molecular underpinnings of frailty and its impact on long-term outcomes. In this issue of Transplantation, Singer et al5 further advance the field by providing evidence of a temporal association between frailty in lung transplant recipients and the subsequent development of chronic lung allograft dysfunction (CLAD).5 In a single-center, retrospective cohort analysis, 231 patients transplanted between 2010 and 2017 were assessed every 3 to 6 mo in the ambulatory setting for frailty, as captured by the Short Physical Performance Battery (SPPB) tool. Findings were correlated to the development of CLAD by 48 mo posttransplant (International Society for Heart and Lung Transplantation consensus criteria) using Cox proportional cause-specific hazards models, adjusting for age at transplant, sex, race, lung disease diagnosis, body mass index, cytomegalovirus serostatus, and episodes of acute cellular rejection (2 separate analyses for ≥A2 and ≥A1 were performed to control for receipt of corticosteroids).6 The reverse association of CLAD with subsequent frailty was also examined via a conditional logistic regression analysis of a matched cohort of patients with and without CLAD. The authors found that within the first 3 y posttransplant, frailty was associated with an adjusted increased risk of subsequent CLAD development of 75% (crude hazard ratio 1.76; 95% confidence interval, 1.05-2.92, P = 0.031). Moreover, each 1-point worsening of the SPPB frailty score was associated with a 10% increased risk of CLAD. CLAD did not seem to be associated with subsequent development of frailty (odds ratio 4.0; 95% confidence interval, 0.4-197.0; P = 0.375). There are several strengths to this study. Foremost, this is the first study to examine an association between frailty in the post–lung transplantation setting and CLAD. In addition, there was a high rate of patient follow-up and adherence to the study protocol. It is laudable that assessing for parameters that comprise the SPPB is a routine part of the posttransplant clinic visit template at the University of California San Francisco and serves as a model for other transplant centers. The main limitations of this study result from its single-center, retrospective design. Whether findings are generalizable to other lung transplant centers is unclear. The University of California San Francisco cohort seems to overall be a sicker cohort (slightly higher proportion of patients with interstitial lung disease [~70%], median lung allocation score of 52.0), with a larger representation of Hispanic patients (13.9%). Moreover, there may be additional bias in the study because of center-specific practice patterns around management of immunosuppression, acute cellular rejection, antibody-mediated rejection, or other clinical events after transplant. Furthermore, given that the authors are leaders in frailty in lung transplantation, outcome biases, such as increased awareness and treatment of frailty, may be present. Finally, it is important to remember that causal associations between frailty and CLAD have not been elucidated and are (understandably) beyond the scope of this work. This analysis does engender several important follow-up questions, including (1) is there a causal relationship between frailty and CLAD; (2) how do immunosuppression and anti-inflammatory therapies (azithromycin, montelukast, extracorporeal photopheresis) ameliorate the relationship between frailty and CLAD, if at all; (3) what is the influence of pretransplant frailty severity on CLAD development; and (4) are there genetic predispositions to frailty-associated CLAD? The findings of Singer et al are highly relevant. CLAD is the main cause of allograft dysfunction and death in lung allograft recipients beyond the first year posttransplant. Moreover, >50% of lung transplant recipients will develop CLAD within 3 to 5 y posttransplant. Because there are currently no existing cures for CLAD, management hinges largely on prevention.6 Identifying CLAD risk factors and their contribution to the pathogenesis of CLAD is pivotal to improving long-term survival following lung transplantation. In this regard, the work of Singer et al solves 1 piece of the puzzle as to how frailty increases posttransplant mortality, likely in part by potentiating CLAD pathways. A relationship between frailty and CLAD is biologically plausible because they are both the result of proinflammatory states. Frailty in the general population is associated with increased levels of serum interleukin (IL)-6, C-reactive protein, tumor necrosis factor (TNF)-α, and TNF-α-RII and correlates with frailty severity.7 Proinflammatory biomarkers, including IL-6, insulin-like growth factor-1, TNF-α-R1, and leptin, have been shown to be increased in frail lung transplant candidates as well.1 In fact, a proinflammatory state is considered the driving force behind aging and frailty and is aptly named “inflammaging.”8 Similarly, the early phases of CLAD are hallmarked by upregulation of a proinflammatory cascade of “type 1” cytokines, including TNF-α and IL-6, among other responses.9,10 The finding of Singer et al that frailty and subsequent CLAD development are associated is provocative and important. A deeper understanding of the molecular underpinnings of this relationship has the potential to improve survival and quality of life in lung transplant recipients and should be further explored.