The effect of known and unknown confounders on the relationship between air pollution and Covid-19 mortality in Italy: A sensitivity analysis of an ecological study based on the E-value

Back in December 2019, the novel coronavirus disease 2019 (Covid-19) started rapidly spreading worldwide, especially in Italy that was among the most affected countries. The geographical distribution of air pollution and Covid-19 mortality in Italy suggested atmospheric pollution as a worsening factor of severe Covid-19 health outcomes. The present nationwide ecological study focused on all 107 Italian territorial areas, aiming to assess the potential association between Particulate Matter concentration, less than 2.5 μm in diameter (exposure), and Covid-19 mortality rate (outcome) throughout 2020, by looking at 28 potential confounders. A potential positive association between exposure and outcome was observed when performing a multivariate regression analysis with a Negative Binomial model, suggesting that an increase of 1 μg/m³ in the exposure is associated with an increase of 9.0% (95% CI: 6.5%-11.6%) in the average Covid-19 mortality rate, conditional on all 28 potential confounders. A sensitivity analysis, based on the E-value, shows that a hypothetical unmeasured confounder would have to be associated with both PM_2.5 concentration and Covid-19 mortality rate by a rate ratio of at least 1.40-fold each to explain away the exposure-outcome association, conditional on all 28 covariates included in the main analysis model. Moreover, the Observed Covariate E-value (OCE) was reported to provide a contextualization of the E-value on the observed covariates included in the study. The OCE sensitivity analysis shows that a set of unknown confounders similar in size and magnitude to the set of the considered climatic factors could potentially explain away the estimated exposure-outcome association. Consequently, the role of climatic factors in the Covid-19 pandemic is worth of further investigation.