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 (PM 10 ) with nitrogen dioxide (NO 2 ) and ozone (O 3 ) on 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 PM 10 , NO 2 and O 3 in 2019 from chemical-transport and random-forest models. We estimated 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: 41,065 individuals were infected, 5,203 were hospitalized and 1,543 died from COVID-19 during follow-up. Mean PM 10 was 1.6 times higher and NO 2 2.6 times higher than WHO limits, with wide gradients between urban and non-urban areas. PM 10 and NO 2 were positively associated with SARS-CoV-2 infectivity and mortality, and PM 10 with hospitalizations in urban areas. Interaction analyses estimated that the effect of PM 10 (per 3.5 µg/m 3 ) on infectivity was strongest in urban areas (HR=1.12, 95%CI:1.09-1.16), corresponding to 854 additional cases per 100,000 person-years, and in areas at high NO 2 co-exposure (HR=1.15, 1.08-1.22). At higher levels of PM 10 co-exposure the protective association of ozone reversed (HR=1.32, 1.17-1.49), yielding to 278 additional cases per µg/m 3 increase in O 3 . We estimated similar interactive effects for severity endpoints.

Conclusions: We estimate that interactive effects between pollutants exacerbated the burden of SARS-CoV-2 pandemic in urban areas.