Interactive effects of long-term exposure to air pollutants on SARS-CoV-2 infection and severity: a northern Italian population-based cohort study

Background: We examined interactions, to our knowledge not yet explored, between long-term exposures to particulate matter (PM10) with nitrogen dioxide (NO2) and ozone (O3) on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectivity and severity. Methods: We followed 709,864 adult residents of Varese Province from 1 February 2020 until the first positive test, COVID-19 hospitalization, or death, up to 31 December 2020. We estimated residential annual means of PM10, NO2, and O3 in 2019 from chemical transport and random-forest models. We estimated the interactive effects of pollutants with urbanicity on SARS-CoV-2 infectivity, hospitalization, and mortality endpoints using Cox regression models adjusted for socio-demographic factors and comorbidities, and additional cases due to interactions using Poisson models. Results: In total 41,065 individuals were infected, 5203 were hospitalized and 1543 died from COVID-19 during follow-up. Mean PM10 was 1.6 times higher and NO2 2.6 times higher than WHO limits, with wide gradients between urban and nonurban areas. PM10 and NO2 were positively associated with SARS-CoV-2 infectivity and mortality, and PM10 with hospitalizations in urban areas. Interaction analyses estimated that the effect of PM10 (per 3.5 g/m3) on infectivity was strongest in urban areas [hazard ratio (HR) = 1.12; 95% CI =1.09, 1.16], corresponding to 854 additional cases per 100,000 person-years, and in areas at high NO2 co-exposure (HR = 1.15; 1.08, 1.22). At higher levels of PM10 co-exposure, the protective association of O3 reversed (HR =1.32, 1.17, 1.49), yielding 278 additional cases per g/m3 increase in O3. We estimated similar interactive effects for severity endpoints. Conclusions: We estimate that interactive effects between pollutants exacerbated the burden of the SARS-CoV-2 pandemic in urban areas.