Viral and Symptom Rebound in Untreated COVID-19 Infection

There are reports of viral and symptom rebound in COVID-19 patients after Paxlovid treatment, but the natural trajectory of viral and symptom improvement in untreated COVID-19 has been insufficiently documented. In this study, we evaluated incidence of viral and symptom rebound in untreated outpatients with mild-moderate COVID-19. The study population included 568 participants enrolled who received placebo in the ACTIV-2 trial. Anterior nasal swabs were collected on days 0-14, 21, and 28. Participants recorded the severity of 13 targeted symptoms daily. Viral rebound was defined as ≥0.5 log10 viral RNA copies/mL increase and symptom rebound was defined as a 4-point total symptom score increase from baseline. Viral rebound occurred in 12% of participants, while symptom rebound occurred in 27% of participants after initial symptom improvement and in 10% after symptom resolution. Viral rebound was more common in older participants and symptom rebound more common with higher baseline RNA levels and symptom scores. The combination of high-level viral rebound to ≥5.0 log10 RNA copies/mL and symptom relapse after initial improvement was observed in 1-2% of participants. Viral RNA rebound or symptom relapse in the absence of antiviral treatment is common, but the combination of high-level viral and symptom rebound is rare.