Target Trial Emulation of SARS-CoV-2 Infection Versus No Infection and Risk of Post-COVID-19 Conditions in the Omicron Variant Versus Prior Eras.

Ioannou GN, Berry K, Rajeevan N, Li Y, Yan L, Huang Y, Bui D, Hynes DM, Rowneki M, Hickok A, Niederhausen M, Shahoumian TA, Bohnert A, Boyko EJ, Korpak A, Fox A, Baraff A, Iwashyna TJ, Maciejewski ML, Smith VA, Berkowitz TSZ, Pura JA, Hebert P, Wong ES, O'Hare AM, Osborne TF, Viglianti EM, Aslan M, Bajema KL. Target Trial Emulation of SARS-CoV-2 Infection Versus No Infection and Risk of Post-COVID-19 Conditions in the Omicron Variant Versus Prior Eras. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2025 Aug 1; 81(1):10-19, DOI: 10.1093/cid/ciaf087.

Related HSR&D Project(s)

• C19 21-279 – COVID-19 Observational Research Collaboratory - Long-Term Outcomes (LTO) Study

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Abstract:

BACKGROUND: Coronavirus disease 2019 (COVID-19) has been linked to the development of post-COVID-19 conditions (PCCs). We investigated whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection increases the risk of selected PCCs or death up to 1 year after infection, separately in the wild-type (WT), Alpha-transition, Delta, and Omicron eras and by vaccination status. METHODS: We used health records of the Veterans Health Administration to emulate a hypothetical target trial of SARS-CoV-2 infection versus no infection. Veterans who tested positive for SARS-CoV-2 between March 2020 and April 2022 (n = 430 160) were matched 1:1 to veterans who had not tested positive for SARS-CoV-2. All-cause mortality and cumulative incidence of 32 potential PCCs were ascertained at 31-180 and 181-365 days after infection or matched index date. RESULTS: From 31 to 180 days, the cumulative incidence of death and all organ-level PCCs was greater in infected versus uninfected participants, with cumulative incidence differences lower in the Omicron than in the WT era and lower in vaccinated than in unvaccinated persons. In the Omicron era, the cumulative incidence of death and most PCCs from day 181-365 were higher in infected than in uninfected participants only among unvaccinated but not among vaccinated persons. CONCLUSIONS: Excess burden of PCCs and mortality persisted 31-180 days after infection in the Omicron era, albeit at a lower level than in the WT and Delta eras. Excess burden of mortality and most PCCs was much lower 181-365 days after infection and was observed in the Omicron era only among unvaccinated persons, suggesting a protective effect of vaccination.