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

Abstract

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 log₁₀ RNA copies/mL from the immediately preceding time point to a viral load of 3.0 log₁₀ copies/mL or higher. High-level viral rebound was defined as an increase of at least 0.5 log₁₀ RNA copies/mL to a viral load of 5.0 log₁₀ 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.

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

There have been reports of rebound of both SARS-CoV-2 virus and symptoms after receipt of nirmatrelvir–ritonavir for the treatment of COVID-19. Using prospectively obtained data from patients receiving placebo in a large COVID-19 “platform” trial, the authors studied the natural history of rebound in the absence of antiviral therapy.

Figure 1.. Heat map of symptom score rebound after study enrollment (primary analysis definition).

The heat map shows participants with symptom rebound (≥4-point increase in symptom score) after initial symptom improvement after study enrollment. Individual participants are shown in rows, and study days are shown in columns. Red squares represent days meeting symptom rebound criteria, orange squares days of hospitalization, blue squares days that did not meet symptom rebound criteria, and gray squares days on which study diaries were not collected. ID = identification number.

Figure 2.. Description of AN SARS-CoV-2 RNA rebound after study enrollment (primary analysis definition).

AN = anterior nasal. Left. Bar graph shows percentage of participants having AN SARS-CoV-2 RNA rebound ≥0.5 log₁₀ copies/mL at any follow-up time point after study enrollment. The frequencies of viral rebound were assessed with a minimum rebound viral load of ≥3.0, ≥4.0, ≥5.0, or ≥6.0 log₁₀ RNA copies/mL. Center and right. These graphs show AN SARS-CoV-2 RNA in log₁₀ copies/mL by study day in rebounders and nonrebounders, respectively. The thick black lines show median AN SARS-CoV-2 RNA copies/mL for each day. The y-axes show AN SARS-CoV-2 RNA in log₁₀ copies/mL, whereas the x-axes denote study day.