Symptom Trajectories and Long-Term Sequelae of COVID-19: A Matched Case–Control Study with Population-Based Controls

Background/Objectives: Post-COVID-19 condition involves heterogeneous, multisystem symptoms with uncertain recovery. We characterized symptom trajectories from hospitalization to approximately 4 weeks and to 6–8 months and compared the 6–8-month symptom burden with season-matched controls, accounting for serology-identified, previously unrecognized infections. Methods: An individually pair-matched case–control study of adults with RT-PCR–confirmed SARS-CoV-2 and population controls from the Bialystok PLUS cohort, matched on age, sex and a two-month visit window, was performed. All participants underwent anti-nucleocapsid serology. Hospitalized cases were reassessed at approximately 4 weeks and 6–8 months. Cross-sectional outcomes used non-parametric tests and multivariable regression; longitudinal change used paired tests and generalized estimating equations. Results: We included 402 adults (201 post-COVID-19; 201 controls). In hospitalized cases, respiratory symptoms declined rapidly by approximately 4 weeks and remained low at 6–8 months; smell/taste recovered more slowly; fatigue improved modestly; anxiety changed minimally. At 6–8 months, total symptom counts were higher in post-COVID-19 than in controls (median 4 vs. 2), with serology-positive controls intermediate (median 3). Excess burden was concentrated in non-respiratory domains (fatigue, neurocognitive, cardiovascular, and dermatologic), whereas respiratory differences were not significant. In the multivariable model, female sex remained an independent predictor of higher multisystem burden, whereas age, body mass index, hospitalization, and acute biomarker severity were not associated. Conclusions: Six to eight months after symptomatic COVID-19, multisystem symptom burden remains substantial relative to season-matched controls, despite substantial resolution of respiratory complaints. Serology-based identification of previously unrecognized infections indicates an intermediate burden and can guide targeted follow-up.