Natural History of Self-reported Symptoms Following SARS-CoV-2 Infection: A Target Trial Emulation in a Prospective Community-Based Cohort

Background: The natural history of symptoms after SARS-CoV-2 infection remains uncertain because many studies are not representative, ignore background symptom prevalence, lack longitudinal tracking, and omit appropriate controls. Using a prospective, community-based cohort with repeated symptom measures, we estimated post infection risks of long COVID symptoms versus contemporaneous uninfected controls. Methods: We analyzed the CHASING COVID Cohort, a U.S. longitudinal study with surveys and serology (March 2020 to December 2023). Infection status (January 2021 to December 2022) was determined from self-reported PCR/antigen results, serology, or CSTE 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 pre-infection, assessed overall and within three clusters (neurological, autonomic, exercise intolerance) at 4 to 8 and 9 to 12 months post infection. Inverse probability of treatment and censoring weights adjusted for confounding and informative loss to follow up. Results: The analysis included 1,055 infected and 52,310 uninfected person-trials. At 4 to 8 months, the adjusted risk of any long-COVID symptom was 22.6% (95% CI 20.5, 24.8) among infected versus 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 to 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: SARS-CoV-2 infection was associated with elevated risk of new-onset long-COVID symptoms persisting up to 12 months. Using a national community based cohort, contemporaneous uninfected controls, and target trial emulation clarifies the burden attributable to infection and supports ongoing surveillance and targeted prevention and care.