PROJECT SUMMARY/ABSTRACT The spread of SARS-CoV-2 infection and its associated disease state, COVID-19, has led to a global pandemic. Exposure to per- or polyfluoroalkyl substances (PFAS) is associated with reduced immune response, but its effect on COVID-19 is not known. We have a time-sensitive opportunity to determine the effect of serum PFAS on COVID-19, building on a unique statewide firefighter testing program for SARS-CoV-2 antibodies. Our long- term goal is to identify health risks of PFAS mixtures. Our objective in this application is to evaluate the effects of PFAS exposure levels in firefighters in regards to the severity of and immune response to COVID-19 infection. Our hypotheses are that increased PFAS serum concentrations will increase the severity of COVID-19 infection and reduce post-recovery serologic titers, which could thereby increase risk of later re-infection. We will test these hypotheses through two specific aims: 1) Determine the association of serum PFAS concentrations with infection severity; and 2) Determine the association of serum PFAS with SARS-CoV-2 antibody titers. For aim 1, recruiting from our state registry, we will enroll 100 Tucson and Phoenix firefighters with positive SARS-CoV- 2 IgM and/or IgG antibodies, and collect and analyze their serum for PFAS. Using an online survey instrument completed at the time of biological sample collection, we will obtain information on whether the subjects had COVID-19 infection(s) confirmed by diagnostic testing, extent of symptoms (if any) consistent with COVID-19 infection, and whether they were hospitalized. We will evaluate the association between serum PFAS and: 1) severity of symptoms; 2) symptomatic vs. asymptomatic COVID-19 infection; and 3) hospitalization. For aim 2, we will repeat SARS-CoV-2 IgG testing after five months and ten months in all firefighters enrolled in the study to measure changes in immune response and to test the association of PFAS levels and longitudinal changes in IgG using generalized linear regression models that account for repeated measures. At study completion, we will have documented the effects of PFAS exposure on the likelihood of a symptomatic COVID-19 infection and symptom severity in a highly exposed population, as well as effects of PFAS exposure on the subsequent immune response persistence. The proposed research is significant given the potential for PFAS exposure to increase the risk of already severe health consequences of COVID-19 and to reduce long-term immune response. The proposed research is innovative as it is the first to our knowledge to determine the association between serum PFAS levels and COVID-19.

PROJECT NARRATIVE Exposure to per- and polyfluoroalkyl substances PFAS has the potential to significantly worsen SARS-CoV-2 (COVID-19) infection and shorten the period of subsequent immunity. Firefighters have increased serum PFAS levels and are at high risk of COVID-19. This proposed research will document the effects of PFAS exposure on COVID-19 severity and the duration of the subsequent immune response.