Symptom and Viral Rebound in Untreated SARS-CoV-2 Infection.

Background: Although symptom and viral rebound have been reported after nirmatrelvir-ritonavir treatment, the trajectories of symptoms and viral load during the natural course of COVID-19 have not been well described.
Objective: To characterize symptom and viral rebound in untreated outpatients with mild to moderate COVID-19.
Design: Retrospective analysis of participants in a randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04518410).
Setting: Multicenter trial.
Patients: 563 participants receiving placebo in the ACTIV-2/A5401 (Adaptive Platform Treatment Trial for Outpatients With COVID-19) platform trial.
Measurements: Participants recorded the severity of 13 symptoms daily between days 0 and 28. Nasal swabs were collected for SARS-CoV-2 RNA testing on days 0 to 14, 21, and 28. Symptom rebound was defined as a 4-point increase in total symptom score after improvement any time after study entry. Viral rebound was defined as an increase of at least 0.5 log ₁₀ RNA copies/mL from the immediately preceding time point to a viral load of 3.0 log ₁₀ copies/mL or higher. High-level viral rebound was defined as an increase of at least 0.5 log ₁₀ RNA copies/mL to a viral load of 5.0 log ₁₀ copies/mL or higher.
Results: Symptom rebound was identified in 26% of participants at a median of 11 days after initial symptom onset. Viral rebound was detected in 31% and high-level viral rebound in 13% of participants. Most symptom and viral rebound events were transient, because 89% of symptom rebound and 95% of viral rebound events occurred at only a single time point before improving. The combination of symptom and high-level viral rebound was observed in 3% of participants.
Limitation: A largely unvaccinated population infected with pre-Omicron variants was evaluated.
Conclusion: Symptom or viral relapse in the absence of antiviral treatment is common, but the combination of symptom and viral rebound is rare.
Primary Funding Source: National Institute of Allergy and Infectious Diseases.