Natural history of self-reported symptoms following SARS-CoV-2 infection: A target trial emulation in a prospective community-recruited cohort

BACKGROUND: Using a prospective, community-recruited cohort with data on background symptom prevalence and repeated longitudinal symptom assessments, we estimated postinfection risks of long Coronavirus disease (COVID) symptoms compared with contemporaneous uninfected controls. METHODS: We analyzed the CHASING COVID Cohort, a US longitudinal study with surveys and serology (March 2020-December 2023). Infection status (January 2021-December 2022) was determined from self-reported PCR/antigen results, serology, or Council of State and Territorial Epidemiologists probable criteria. We emulated 24 monthly target trials comparing individuals newly infected at time zero with those remaining uninfected. Outcomes were new-onset long-COVID symptoms not reported preinfection, assessed overall and within three clusters (neurological, autonomic, and exercise intolerance) at 4-8 and 9-12 months postinfection. Inverse probability of treatment and censoring weights adjusted for confounding and informative loss to follow-up. RESULTS: The analysis included 1055 infected and 52,310 uninfected person-trials. At 4-8 months, the adjusted risk of any long-COVID symptom was 22.6% (95% CI, 20.5-24.8) among infected vs 11.3% (11.1-11.5) among uninfected (adjusted risk difference [aRD], 11.3% [9.2-13.5]; adjusted risk ratio [aRR], 2.01 [1.81-2.20]). At 9-12 months, risks were 19.2% (17.0-21.3) vs 12.4% (12.2-12.7) (aRD, 6.7% [4.6-8.9]; aRR, 1.54 [1.37-1.72]). Across all three clusters, infected participants had consistently higher risks at both intervals. CONCLUSIONS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was associated with an elevated risk of new-onset long-COVID symptoms persisting up to 12 months. Using a national community-recruited cohort, contemporaneous uninfected controls, and target-trial emulation clarifies the burden attributable to infection and supports ongoing surveillance and targeted prevention and care.