Persistence of Long COVID Symptoms Two Years After SARS-CoV-2 Infection: A Prospective Longitudinal Cohort Study

Background/objectives: Millions of individuals worldwide continue to experience symptoms following SARS-CoV-2 infection. This study aimed to assess the prevalence and phenotype of multi-system symptoms attributed to Long COVID-including fatigue, pain, cognitive-emotional disturbances, headache, cardiopulmonary issues, and alterations in taste and smell-that have persisted for at least two years after acute infection, which we define as "persistent Long COVID". Additionally, the study aimed to identify clinical features and blood biomarkers associated with persistent Long COVID symptoms.

Methods: We sent a detailed long COVID symptoms questionnaire to an existing cohort of 1258 vaccinated adults (age 18-79 years) who had mild infection (e.g., non-hospitalized) SARS-CoV-2 Delta variant 2 years earlier. These individuals had comprehensive datasets, including blood samples, available for further analysis. We estimated prevalence of persistent long COVID two years post-infection using weighted adjustment (Horvitz-Thompson estimator) to overcome reporting bias. Multivariable logistic regression models were used to determine association of clinical features and blood biomarkers (pre-infection SARS-CoV-2 RBD-IgG, SARS-CoV-2 neutralizing antibodies, and pre-infection and post-infection neurofilament light) with prevalence of persistent long COVID.

Results: N = 323 participants responded to the survey, of whom N = 74 (23%) reported at least one long COVID symptom that had persisted for two years after the acute infection. Weighted prevalence of persistent long COVID symptoms was 21.5% (95% CI = 16.7-26.3%). Female gender, smoking, and severity of acute COVID-19 infection were significantly associated with persistent Long COVID. The blood biomarkers assessed were not significantly associated with persistent Long COVID.

Conclusions: Among vaccinated adults two years after mild infection with Delta variant SARS-CoV-2, persistent symptoms attributed to Long COVID are extremely common, certain subgroups are at higher risk, and further research into biological mechanisms and potential treatment targets is needed.