The goal of lung transplantation is to improve quality of life (QOL) and extend survival for patients with advanced lung disease. The degree to which individual lung transplant recipients achieve these goals is highly variable. To improve the overall success of lung transplant, it is necessary to identify factors beyond allograft function that determine key patient-centered outcomes. Patients with advanced organ failure, including lung disease, commonly are frail. While it was initially identified in elderly individuals, frailty occurs in medical and surgical patients across the age spectrum, increasing their risk for poor outcomes. Notably, frailty is a dynamic rather than a static state. In fact, most lung transplant candidates with frailty resolve it within 6 months after transplant, suggesting their frailty was largely driven by lung failure. However, in approximately 20% of patients, frailty persists or newly emerges after lung transplant. For a study published in Thorax, we and our colleagues aimed to determine if frailty after transplant was associated with health-related QOL (HRQOL) and mortality in lung transplant recipients and to also examine potential causes of frailty after transplant.
We conceptualized frailty as the result of physiological dysregulation that unfolds over time. Pathological changes associated with advanced lung disease, such as chronic inflammation, cause functional limitations that can be measured, like decreased lung function and muscle weakness. Similarly, the frail phenotype is a functional limitation that can be measured. Lung transplantation, with its associated need for chronic immunosuppression, can also cause pathological changes that can induce persistent or emergent frailty, which we refer to as transplant-related frailty.
To assess this pathological process over time, we measured frailty and HRQOL repeatedly, before and up to 3 years after lung transplant, and followed the survival of a cohort of adults who underwent lung transplant at the University of California, San Francisco between 2010 and 2017. We also assessed whether four specific pathological factors that are thought to cause frailty and that can be induced by transplantation—sarcopenia, obesity or underweight, malnutrition, and renal dysfunction –were associated with the development of frailty after transplant. We measured frailty using the short physical performance battery, an aggregate score of gait speed, balance, and chair stands that ranges from 0 to 12, with higher numbers indicating less frailty. We considered the entire score range and a binary definition of frail (score ≤7) and not frail (score >7). Because HRQOL is multidimensional, we used 5 instruments to measure generic-physical HRQOL (SF12-PCS), generic-mental HRQOL (SF12-MCS), respiratory-specific HRQL (AQ20-R), and health-utility (EuroQoL 5-dimension).
Among 259 lung recipients, 21% were frail at some point in the first 3 years after transplant and 18% died in the first 4 years. After adjusting for patient characteristics that included age, sex, race, and allograft function, being frail at any point after transplant was associated with significantly lower generic-physical HRQOL and health-utility. Frailty was also associated with a 2.5-fold increase in the risk of death during the first 4 years after transplant (hazard ratio [HR], 2.51; 95% confidence interval [CI], 1.12-5.23). Further, every 1-point worsening in frailty was associated with an average 13% increase in the adjusted risk of death (HR, 1.13; 95% CI, 1.04-1.23). We found that muscle weakness (a component of sarcopenia), obesity, underweight, hypoalbuminemia, and renal dysfunction were predictors of the development of frailty (Table).
The consistent and independent associations between transplant-related frailty with decreased HRQOL and survival suggest that frailty is a clinical marker that may help the early identification of patients at risk for poor outcomes. Since frailty is reversible, research focused on the efficacy of timely interventions to mitigate pathological changes is urgently needed. Targeting frailty may improve the overall success of lung transplantation.