Abstract
BACKGROUND: A large share of SARS-CoV-2 infections now occur among previously infected individuals. In this study, we sought to determine whether prior infection modifies disease severity relative to no prior infection. METHODS: We used data from first and second COVID-19 episodes in the National COVID Cohort Collaborative, a nationwide collection of de-identified electronic health records. We used nested logistic regressions of monthly cohorts weighted on the inverse probability of prior infection to assess risk of hospitalization, death, and increased severity in the first versus second infection cohorts. RESULTS: We included a total of 2,058,274 individuals in the analysis, 147,592 of whom had two recorded infections. The impact of prior infection differed meaningfully between months. Prior infection was largely protective prior to March 2022, with odds ratios (ORs) as low as 0.66 (95% confidence interval: 0.51 to 0.86) in November 2021 for hospitalization. and as low as 0.23 (0.06 to 0.86) in June 2021 for death. However, prior infection was associated with an increased risk of hospitalization and death, mostly after March 2022 when the ORs were as high as 1.87 (1.26 to 2.80) and 2.99 (1.65 to 5.41) in April 2022, respectively. The overall OR for more severe disease was 1.06 (1.03 to 1.10) among previously infected individuals. CONCLUSION: In the pandemic's first two years, previously infected patients generally had less severe disease than people without prior infection. During the Omicron era, however, previously infected patients had the same or worse severity of disease as patients without prior infection.