Abstract
BackgroundFrailty, a multidimensional syndrome of decreased physiological reserve, is associated with adverse health outcomes, but its relationship with a broad spectrum of pulmonary diseases remains incompletely understood. This study aimed to systematically evaluate the associations between frailty and multiple pulmonary diseases and their multimorbidity patterns.MethodsWe analyzed 146,747 participants from the UK Biobank. Frailty was quantified using frailty index (FI) and categorized into non-frail, pre-frail, and frail groups. Outcomes included chronic obstructive pulmonary disease (COPD), asthma, interstitial lung disease (ILD), lung cancer, their overlap syndromes, and pulmonary-related mortality. Cox proportional hazards models with inverse probability of treatment weighting estimated hazard ratios (HRs) and 95% confidence intervals, adjusting for demographic, lifestyle, environmental, and clinical covariates with competing risk analyses performed using Fine-Gray models. Non-linear associations were assessed using restricted cubic splines, and E-values evaluated robustness to unmeasured confounding. Mediation analyses based on UK Biobank Pharma Proteomics Project (UKB-PPP) identify protein signatures associated with frailty-disease relationships.ResultsFrail individuals showed higher incidence of multiple pulmonary outcomes compared with non-frail and pre-frail participants. Dose-response analyses revealed non-linear associations, with risk elevation evident even at pre-frailty (FI = 0.237) for asthma-COPD overlap. Mediation analyses identified WFDC2 and CXCL17 as proteins associated with both frailty and multiple pulmonary outcomes, including ILD and lung cancer.ConclusionFrailty is associated with a higher incidence of multiple pulmonary diseases and multimorbidity patterns. These associations may be partly accounted for by shared protein signatures. Frailty may serve as a marker for risk stratification in respiratory health.