Immune Status and Mortality in Smokers, ex-Smokers and never-Smokers: The Ludwigshafen Risk and Cardiovascular Health Study

BACKGROUND Elevated leukocyte counts are associated with cardiovascular disease. Smoking induces inflammation and alters levels of leukocyte subtypes. Our aim was to investigate the effect of smoking on circulating immune cells and their association with mortality. METHODS Lymphocyte subtypes were identified by flow cytometry of fluorescent-labeled cells. We analysed the association of leukocytes with mortality using Cox regression and assessed their effect on risk prediction based on principle components (PCs) using area-under-the-ROC-curve and net-reclassification in 2173 participants from the Ludwigshafen Risk and Cardiovascular Health study, a prospective case-control study in patients who underwent coronary angiography. RESULTS Numbers of T cells, monocytes and neutrophils were higher and natural killer cells were lower in smokers compared with never-smokers. In never-smokers, lymphocyte counts were inversely associated with mortality while a positive association was observed for neutrophils. The neutrophil-to-lymphocyte-ratio (NLR) had the strongest association in never-smokers with a HR (95% CI) of 1.43 (1.26-1.61). No associations were found in smokers. Adding the first five PCs or the NLR to a risk prediction model based on conventional risk factors did not improve risk prediction in smokers, but significantly increased the AUC from 0.777 to 0.801 and 0.791, respectively, in never-smokers. CONCLUSIONS Lymphocyte counts were inversely associated with mortality in never-smokers but not in active smokers. Markers of innate immunity, namely total neutrophils and CD11b+/CD18+ and CD31+/CD40- granulocytes, were directly associated with mortality. Adding markers of immune function like PCs or the NLR to basic risk models improved risk prediction in never-smokers only.