Smoking exposures and mortality risk in individuals with idiopathic pulmonary fibrosis: a UK Biobank cohort study

Abstract

Background Smoking and secondhand smoke (SHS) exposures are established modifiable risk factors for premature mortality, but their joint associations with recorded idiopathic pulmonary fibrosis (IPF) remain uncertain. We examined active and passive smoking exposures in relation to all-cause and cause-specific mortality and evaluated departures from additivity with recorded IPF history. Methods This prospective UK Biobank cohort included 270,644 participants. Exposures comprised baseline smoking status, cumulative pack-years, maternal smoking around birth, adult SHS, and a composite passive SHS indicator. Multivariable Cox models, additive and multiplicative interaction analyses, and restricted cubic spline models were used after adjustment for demographic, socioeconomic, lifestyle, and genetic covariates. Results During a median follow-up of 13.8 years, 20,959 deaths occurred. Ever-recorded IPF history was associated with all-cause mortality (HR 4.255, 95% CI 3.937–4.597), and active and passive smoking measures were also associated with mortality. In the additive interaction analyses, a positive departure from additivity was observed only between maternal smoking around birth and recorded IPF in relation to respiratory mortality (RERI 16.969, 95% CI 2.935–31.002; AP 0.248, 95% CI 0.082–0.414; SI 1.337, 95% CI 1.068–1.673). Corresponding positive RERI estimates were observed in analyses restricted to White participants, among participants with complete covariate data, and after excluding deaths occurring within the first 2 years of follow-up. The confidence intervals for the other RERI estimates in the primary analysis included zero. Dose–response associations were nonlinear among participants without recorded IPF and approximately linear among those with recorded IPF, although estimates in the latter group were less precise. Conclusion Active and passive smoking measures and ever-recorded IPF history were associated with mortality in this cohort. Evidence for positive additive interaction was confined to maternal smoking around birth and respiratory mortality and should be interpreted as hypothesis-generating. The observational findings do not establish causal or biological synergy and require replication in independent cohorts.