The Influence of Selection Bias on Identifying an Association between Allergy Medication Use and SARS-CoV-2 Infection

Abstract

Background: Medications to prevent and treat SARS-CoV-2 infection are needed to complement emerging vaccinations. Recent in vitro studies suggested that certain allergy medications could prevent SARS-CoV-2 infection so we sought to characterize this relationship using existing electronic health record (EHR) data.Methods: We analyzed associations of three allergy medications (cetirizine, diphenhydramine or hydroxyzine) with testing negative for SARS-CoV-2 infection, and measuring also the potential effect of selection bias on these associations. We used EHR data from 230,376 patients (18 years+) who visited outpatient clinicians in a single, large academic center at least once but were never hospitalized (10/1/2020-6/1/2020). Main exposures included EHR documentation of three allergy medications and allergy, with intermediate outcome of receipt of a SARS-CoV-2 test, and the primary outcome as testing negative. Findings: Testing rates varied by sex, age, race/ethnicity and insurance type. Higher age categories and public insurance were associated with a higher adjusted odds of a negative test, while being Black or Hispanic was significantly associated with test positivity. Allergy diagnosis and use of any of three allergy medications were each associated with a higher likelihood of receiving a test (e.g. diphenhydramine - Odds Ratio (OR) 2.99, 95% Confidence Interval (CI) 2.73, 3.28; cetirizine 1.75 (95% CI 1.60, 1.92)). Among those who were tested, only use of diphenhydramine was associated with a negative SARS-CoV-2 test (adjusted OR = 2.23, 95% CI 1.10, 4.55). However, further analyses revealed that selection bias was likely responsible for the apparent protective effect of diphenhydramine.Interpretation: While EHR-based observational studies can inform a need for interventional trials, this study highlights their limitations. The finding that diphenhydramine was associated with a higher odds of testing negative for SARS-CoV-2 must be interpreted with caution due to selection bias.Funding: The Children’s Miracle Network of the University of Florida partially funded this study.Declaration of Interests: Dr. Rasmussen has served on advisory committees for the Teva Pregnancy Registry and Solriamfetol Pregnancy Registry and has consulted for F. Hoffmann-La Roche AG as a litigation expert. Dr. Ostrov has a patent pending for compounds to prevent and treat COVID-19 and methods of using the same. All other authors have nothing to declare. Ethics Approval Statement: We received human subjects approval from the University of Florida Institutional Review Board.