Background The SARS-CoV-2 Omicron variant has a higher infection rate than previous variants but results in less severe disease. However, the effects of Omicron and vaccination on chest CT findings are difficult to evaluate. Purpose To investigate the effect of vaccination status and predominant variant on chest CT findings, diagnostic scores, and severity scores in a multicenter sample of consecutive patients referred to emergency departments for proven COVID-19. Materials and Methods This retrospective multicenter study included adults referred to 93 emergency departments with SARS-CoV-2 infection according to a reverse-transcriptase polymerase chain reaction test and known vaccination status between July 2021 and March 2022. Clinical data and structured chest CT reports, including semiquantitative diagnostic and severity scores following the French Society of Radiology-Thoracic Imaging Society guidelines, were extracted from a teleradiology database. Observations were divided into Delta-predominant, transition, and Omicron-predominant periods. Associations between scores and variant and vaccination status were investigated with χ² tests and ordinal regressions. Multivariable analyses evaluated the influence of Omicron variant and vaccination status on the diagnostic and severity scores. Results Overall, 3876 patients were included (median age, 68 years [quartile 1 to quartile 3 range, 54-80]; 1695 women). Diagnostic and severity scores were associated with the predominant variant (Delta vs Omicron, χ² = 112.4 and 33.7, respectively; both P < .001) and vaccination status (χ² = 243.6 and 210.1; both P < .001) and their interaction (χ² = 4.3 [P = .04] and 28.7 [P < .001], respectively). In multivariable analyses, Omicron variant was associated with lower odds of typical CT findings than was Delta variant (odds ratio [OR], 0.46; P < .001). Two and three vaccine doses were associated with lower odds of demonstrating typical CT findings (OR, 0.32 and 0.20, respectively; both P < .001) and of having high severity score (OR, 0.47 and 0.33, respectively; both P < .001), compared with unvaccinated patients. Conclusion Both the Omicron variant and vaccination were associated with less typical chest CT manifestations of COVID-19 and lesser extent of disease. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Yoon and Goo in this issue.

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