In this large prospective cohort study, we observed a substantial increase in the risk of developing COPD among frail and prefrail individuals compared to nonfrailty, independent of sociodemographic factors, lifestyles, multiple morbidities, and genetic background. Specifically, frail individuals had a 121% increased risk, while prefrail individuals had a 45% increased risk of developing COPD. Furthermore, our study showed that the PRISm population with frailty had a 4.34 times higher risk of developing COPD compared to those with normal lung function but without frailty. These findings highlight the importance of recognizing and addressing prefrailty and frailty status in COPD prevention, especially in those with PRISm.
Several cross-sectional studies have described the relationship between frailty and COPD, and lung function.[9, 22–24] One study found that 15% of patients with COPD consisted of frail individuals,[9] and there have been reports suggesting that COPD can promote frailty.[11, 23] However, longitudinal evidence is scarce concerning the association between physical frailty and COPD incidence in the general population. Several studies have found cross-sectional associations between frailty and lung function, with frail individuals exhibiting lower FEV1 compared to nonfrail individuals.[24, 25] The Cardiovascular Health Study revealed a 42% increased risk of lung function impairment in frail individuals above 65 years of age compared to nonfrail individuals.[26] Our study, for the first time, provided evidence that both prefrailty and frailty were associated with subsequent increased risk of COPD. Among the five components of physical frailty phenotype, we found that exhaustion, low physical activity, slow gait speed, and low grip strength (but not weight loss) were associated with the incidence of COPD, and the more components present, the higher the risk of developing COPD. Notably, while physical activity has been associated with the incidence of COPD,[27] our study adds that gait speed, grip strength, and exhaustion are also individually associated with COPD incidence, which have not been reported.
PRISm is a common condition, with a prevalence of 11%, and over a 9-year period, 62.2% of individuals transitioned to different lung function states.[13] Our study revealed that the risk of developing COPD in the PRISm population is 3.64 times higher than in individuals with normal lung function. Moreover, we first observed a joint effect between physical frailty and PRISm in COPD development, which suggested that early assessment of physical frailty status and implementation of intervention measures are necessary in the PRISm population for COPD prevention.
Genetic predisposition plays a significant role in COPD development,[14, 20] which was observed in our results regarding PRS and COPD risk. We found that the association of frailty and prefrailty with incident COPD remains significant across different PRS strata, although insignificant interaction term was observed. These findings underscore the importance of frailty management for COPD prevention regardless of genetic predisposition.
The mechanisms underlying the observed association remain unclear. COPD is characterized by airway inflammatory cell infiltration and elevated inflammatory factors. Previous research has shown significantly higher levels of inflammatory factors, including interleukin-6, tumor necrosis factor-alpha, and C-reactive protein, in individuals with frailty and prefrailty.[28] This suggests that inflammation associated with frailty may contribute to the development of COPD. Additionally, cross-sectional studies have revealed that lung function is significantly lower in frail individuals,[24] which could be attributed to the reduction in muscle mass and strength caused by frailty,[29] which may, in turn, affect the normal functioning of respiratory muscles. The reduction in muscle mass and strength may also manifest as slower walking speed and decreased grip strength, both of which are related to COPD progression.
While this study provides the first large longitudinal evidence regarding the relationship between frailty and COPD incidence, there are some limitations to consider. First, information on the transition of frailty status during follow-up could not be reached, which may affect our accurate estimation of the relationship between frailty and COPD. However, as the age of the participants increases during the follow-up process, the probability of developing frailty also increases. This implies that using baseline frailty as an exposure would result in the frailty-COPD association toward null. Second, we determine whether the subjects have developed COPD during follow-up based on ICD-9 or ICD-10, and there may be cases of newly developed COPD being missed. Despite this possibility, the theoretical rate of missed diagnosis is very low due to the regular follow-up and detailed inquiries required for the study population. Third, the definition of PRISm ignores total lung volume and is influenced by bronchodilators, age, small airway diseases, etc. The pathophysiological connection between PRISm and airway obstruction requires further discussion and clarification.