Background: Eosinophils are granulocytes associated with airway inflammation in respiratory disease. Eosinophil production and survival is controlled by interleukin-5: anti-interleukin-5 agents reduce asthma and COPD exacerbation frequency, and response correlates with baseline eosinophil counts. However, causal relationships between eosinophils and other respiratory phenotypes are less studied. Methods: We investigated causality between eosinophils and: lung function, acute exacerbations of COPD (AECOPD), asthma-COPD overlap (ACO), moderate-to-severe asthma, and respiratory infections. We performed Mendelian randomization (MR) using 151 genetic variants from genome-wide association studies of blood eosinophil counts in UK Biobank/INTERVAL, and respiratory data from UK Biobank, using MR methods relying on different assumptions for validity. Multivariable MR using eight blood cell type exposures was performed for outcomes showing evidence of causation by eosinophils. Findings: There was evidence that higher eosinophils reduce FEV1/FVC and FEV1 (weighted median estimator, SD change FEV1/FVC per SD eosinophils: -0.054 [95%CI -0.078,-0.029]. There was also evidence that eosinophils cause ACO (weighted median OR 1.44 [95%CI 1.19,1.74]), and asthma (weighted median OR 1.50 [95%CI 1.23,1.83]). Multivariable MR for FEV1/FVC, FEV1, ACO and asthma suggested that eosinophils were the cell type with the most important effect. Causal estimates of individual variants were heterogeneous, which may arise from pleiotropy. Interpretation: We found evidence that eosinophils reduce lung function, and increase ACO and asthma risk, on average over the set of genetic variants studied. Eosinophils appear to be causal determinants of fixed airflow obstruction among individuals with features of both asthma and COPD.

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