Circulating SARS-CoV-2 RNA detection in acute COVID-19 disease and Post-COVID Condition

Objectives: To determine the clinical significance of circulating plasma SARS-CoV-2 RNA across acute COVID-19 and post-COVID condition (PCC) by investigating prevalence, determinants, and kinetics in a large longitudinal cohort, accounting for hospitalization and vaccination. Methods: We consecutively enrolled individuals with confirmed SARS-CoV-2 infection. Acute COVID-19 was classified as mild, severe, or critical per WHO criteria. PCC was assessed three months post-symptom onset, plasma SARS-CoV-2 RNA (RNAemia) was quantified during acute infection (T0) and at follow-up (T1) by RT-qPCR. Associations between RNAemia and acute disease severity or PCC were evaluated using multivariable logistic regression. RNAemia was analyzed as tertiles, binary detectability, and continuous levels. Results: 442 COVID-19 individuals were included, of whom 195 (44.1%) had mild disease, 161 (36.4%) severe, and 86 (19.5%) critical. At a median of 3.2 (IQR 2.7-3.9) months from symptoms onset, 184/442 subjects were followed up, and 144/184 (78.3%) reported at least one persistent symptom compatible with PCC, most commonly asthenia (22.9%), myalgic pain (26.4%), brain fog (19.4%), dyspnea (31.3%), and cough (42.4%). RNAemia was detected in 67.4% of participants at baseline and in 53.6% at follow-up. RNAemia in the II-III tertiles or any detectable RNAemia were associated with critical COVID-19. Neither baseline nor follow-up RNAemia, were associated with PCC, and results were unchanged in a sensitivity analysis excluding vaccinated individuals. RNAemia trajectories were not associated with PCC, PCC clusters, or upper respiratory tract viral clearance.. Conclusions: SARS-CoV-2 RNAemia was closely linked to acute COVID-19 severity but showed no association with PCC or PCC phenotype which were assessed at 3 months from symptoms onset in a cohort predominantly experiencing severe COVID-19 and hospitalization during acute infection. This dissociation may suggest that viral RNA in the peripheral blood is primarily involved in acute pathogenesis, whereas PCC likely arises from distinct biological mechanisms.