Natural course of post COVID-19 condition and implications for trial design and outcome selection: A population-based longitudinal cohort study

BACKGROUND: Evidence from population-based studies on the longer-term natural course of post COVID-19 condition is limited, but crucial for informing patients and healthcare providers and for effectively designing clinical trials. OBJECTIVES: To evaluate longer-term symptoms and health outcomes within a cohort of SARS-CoV-2 infected individuals. DESIGN: Population-based, longitudinal cohort. SETTING: General population, Canton of Zurich, Switzerland. PATIENTS: 1543 adults with confirmed SARS-CoV-2 infection and 628 adults without infection. MEASUREMENTS: Changes in self-reported health status over time, factors associated with persistence of non-recovery, and prevalence and excess risk of symptoms at 6 and 12 months post-infection compared to non-infected individuals. RESULTS: 25% of SARS-CoV-2 infected individuals did not recover by 6 months. Of those, 67% and 58% also did not recover at 12 and 18 months after infection, respectively. Hospitalization for acute COVID-19, pre-existing fatigue and pain or discomfort, and presence of specific systemic, cardiovascular, or musculoskeletal symptoms at 6 months were associated with persistent non-recovery. Symptom prevalence was higher among infected individuals compared to non-infected individuals at 6 months (adjusted risk difference (aRD)=17%) and 12 months (aRD=20%). aRDs for individual symptoms ranged from 2% to 12%, with the highest excess risks observed for altered taste or smell, post-exertional malaise, fatigue, and reduced concentration and memory. LIMITATIONS: We relied on self-reported assessments and did not assess the effects of vaccination or infection with emerging variants of concern. CONCLUSION: These findings emphasize the need for effective interventions to reduce the burden of post COVID-19 condition. They further demonstrate the importance of using multiple outcome measures and of considering the expected rates of natural recovery and heterogenous patient trajectories in the design and interpretation