New insights into the paradox between smoking and the risk of SARS-CoV-2 infection (COVID-19): insufficient evidence for a causal association

Several previous studies have reported a ‘smoker's paradox’, where smokers appear to be protected against SARS-CoV-2 infection (COVID-19). This claim conflicts with well-established evidence that smokers are generally more vulnerable to respiratory infections. We aimed to validate the association between smoking and SARS-CoV-2 infection in a Dutch population-based cohort study (N=57,833), adjusting for several relevant covariates. Compared to never smokers, we found an increased risk of SARS-CoV-2 infection for former smokers but a reduced risk for current smokers. However, we dissected a possible explanation of the smoker's paradox since we observed that current smokers were more likely to be non-responders to the COVID-19 questions and, more importantly, these non-responders were more likely to have other established risk factors for SARS-CoV-2 infection. To further scrutinize the smoker’s paradox, we applied a modern adaptation of the Bradford Hill criteria for causation to the existing literature. Since we observed a high inconsistency between study results, a high possibility for residual confounding, and no clear evidence for biological plausibility, we conclude that there is insufficient evidence for an inverse association between smoking and SARS-CoV-2 infection. Future studies should include linkage with the confirmed testing results from national healthcare registries to mitigate avoidable bias.