FEV1 Variability as a Novel Mortality Biomarker

New York University School Of Medicine, New York NY

Investigators

Abstract

Lower Baseline-FEV1 (cross sectional forced expiratory volume at one second at the beginning of longitudinal follow-up) and FEV1-slope (decline in FEV1 over longitudinal follow-up) are mortality risk factors in FDNY World Trade Center exposed rescue and recovery workers. During our investigation of FEV1-slope and mortality, we observed increasing FEV1 visit-to-visit variability is a previously unreported mortality risk factor. We define FEV1 visit-to-visit variability as the standard error of the FEV1-slope modeled by linear regression. Each doubling of FEV1 visit-to-visit variability increased mortality hazard by 22% in the FDNY cohort (Hazard ratio (HR) 1.22, 95% confidence interval (CI): 1.13-1.33 p<.001). Similarly, in an independent community-based replication cohort, doubling FEV1 visit-to-visit variability increased mortality hazard by 17% (HR 1.17, 95% CI:1.14-1.20 p<.001). Inhaled corticosteroids and long-acting beta agonists (ICS/LABA) treated lung injury in 2,209/11,745, 18.8% of the cohort. A feasibility study of 284/2,209,12.5% of those treated for more than two years, assessed if FEV1 visit-to-visit variability is useful as a treatment outcome measure after ICS/LABA initiation. We define response to ICS/LABA as a decrease in FEV1 visit-to-visit variability after treatment initiation (ratio pre/post FEV1 visit-to-visit variability >1). Forty percent (113/284) of the patients in the feasibility study responded to ICS/LABA treatment. Compared with treatment non-responders, responders had a trend to 91% lower mortality odds (OR 0.09, 95%CI. 0.01-1.40 p=0.09). These data are consistent with this R21’s hypothesis: FEV1 visit-to-visit variability is a mortality risk factor and ICS/LABA can improve FEV1 visit-to-visit variability. When compared to ICS/LABA non-responders, ICS/LABA responders, who reduce visit-to-visit variability after ICS/LABA initiation, will have lower mortality. AIM1 will assess the sensitivity and specificity of mortality prediction models that already incorporate well-accepted risk factors of baseline-FEV1 and FEV1- slope to test the hypothesis that adding visit-to-visit FEV1 variability improves their sensitivity and specificity. Aim 2, will use patients as their own controls to determine if ICS/LABA treatment reduces FEV1 visit-to-visit variability and will assess if response to ICS/LABA treatment is associated with reduced mortality. If the data developed in this R21 demonstrates that FEV1 visit-to-visit variability is a mortality risk factor and that treatment response is associated with lower mortality after controlling for well-accepted risk factors including baseline- FEV1 and FEV1-slope, then those with elevated FEV1 visit-to-visit variability who have not been treated could have pulmonary evaluation for consideration of ICS/LABA treatment. This grant’s focus on FEV1 visit-to-visit variability is novel and critically important because it may predict mortality and assess treatments to modify outcomes early in the disease course when treatment is more effective.