Abstract
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 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 PM 10 , NO 2 , and O 3 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 PM 10 was 1.6 times higher and NO 2 2.6 times higher than WHO limits, with wide gradients between urban and nonurban 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 [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 NO 2 co-exposure (HR = 1.15; 1.08, 1.22). At higher levels of PM 10 co-exposure, the protective association of O 3 reversed (HR =1.32, 1.17, 1.49), yielding 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 the SARS-CoV-2 pandemic in urban areas.