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B58-07 Breathlessness as a Biomarker of Frailty Independent of Spirometry and Quantitative CT Measurements
Abstract   Peer reviewed

B58-07 Breathlessness as a Biomarker of Frailty Independent of Spirometry and Quantitative CT Measurements

E K Phillips, E A Regan, B J Make, A M Yohannes, K F Hoth, J Bon, G R Washko, R P Bowler, E K Silverman, J D Crapo, …
American journal of respiratory and critical care medicine, Vol.212(Supplement_1), aamag1623065
05/01/2026
DOI: 10.1093/ajrccm/aamag162.3065

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Abstract

Rationale Frailty, a syndrome of vulnerability to stressors, is associated with adverse respiratory outcomes. Clinically practicable biomarkers of prospective frailty risk are lacking. Methods This study included individuals from the Genetic Epidemiology of COPD(COPDGene) study who had a normal baseline six-minute walk distance, baseline quantitative CT and breathlessness measurements, and frailty assessment at the 10-year follow-up. Breathlessness was defined as a modified Medical Research Council (mMRC) Dyspnea Score ≥2. The outcome of frailty was assessed using a modified Fried Frailty Phenotype. Multivariable logistic regression of breathlessness on frailty (compared to robustness) at 10-year follow-up was adjusted for age, sex, smoking status, smoking pack-years, and forced expiratory volume in one second (FEV1) %predicted. Predictive model performance was assessed. Sensitivity analysis was performed in the subgroup with normal baseline spirometry. We additionally adjusted for individual quantitative CT measurements to assess whether associations of breathlessness with frailty persisted independent of CT findings. Measurements evaluated were: emphysema (log10[%LAA-950]), airway wall thickening (Pi10), PA enlargement (pulmonary artery:aorta ratio≥1), and BV5/TBV (blood volume in pulmonary vessels<5mm2/total pulmonary blood volume). To further characterize breathlessness as a frailty risk factor, we evaluated concurrent plasma proteomic data from the SomaScan 1.3k platform. To evaluate quantitative CT features associated with breathlessness, we performed multivariable logistic regression of CT measurements on breathlessness (covariates as above). Results Among 2380 participants (mean[SD] age 59.2[8.1], 48% male), 578(24%) were breathless at baseline. At 10-year follow-up, 868(36%) were robust, 1205(51%) were prefrail, and 307(13%) were frail. Among those with breathlessness, 21% developed frailty (vs 7.1% for non-breathless). In an adjusted model, breathlessness was associated with increased frailty risk (OR[95% CI] 4.5[3.1-6.5], p < 0.001). This model predicted frailty with a C-statistic of 0.84. Breathlessness remained strongly associated with frailty in those with normal baseline spirometry (OR 3.3[1.9-5.8], p < 0.001). Findings persisted in models additionally adjusted for CT measurements. Breathlessness-associated proteins (FDR<0.05) included FABP3 (previously associated with heart disease and sarcopenia) and inflammatory proteins (CRP, complement factors, and IL1RN). Breathlessness associated with PA enlargement (OR 2.1[1.5-3.1], p < 0.001) and BV5/TBV (OR per 1SD: 0.8[0.7-0.9], p < 0.001) in the overall cohort and in the subgroup with normal spirometry. Conclusions Breathlessness was associated with systemic inflammation and pulmonary vascular traits and was a strong predictor of future frailty independent of spirometry. A model combining breathlessness with clinical data had over 80% predictive power for frailty. These findings suggest a role for frailty screening in individuals experiencing breathlessness, regardless of comorbid lung disease. This abstract is funded by: EKP is supported by 5T32HL007427-42. This work was supported by NHLBI grants U01 HL089897 and U01 HL089856 and by NIH contract 75N92023D00011.
 Biomarkers Frailty Regression analysis Spirometry

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