Rebounding of COVID-19 symptoms and viral load are common among untreated COVID-19 patients

By Pooja Toshniwal PahariaReviewed by Benedette Cuffari, M.Sc.Feb 27 2023

In a recent study published in the Annals of Internal Medicine, researchers characterize coronavirus disease 2019 (COVID-19) symptom and viral load rebounds among untreated individuals with mild-to-moderate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in outpatient settings.

Study: Symptom and Viral Rebound in Untreated SARS-CoV-2 Infection. Image Credit: Subbotina Anna / Shutterstock.com

Background

Previous studies have reported cases of COVID-19 symptom rebound following nirmatrelvir-ritonavir therapy. However, the simultaneous occurrence of symptom and SARS-CoV-2 rebounds have been reported among a limited number of individuals or in uncontrolled settings. The trajectories of symptoms and SARS-CoV-2 loads over the course of natural SARS-CoV-2 infection are not well-characterized and require further investigation.

About the study

In the present study, researchers retrospectively analyzed data from the adaptive platform treatment trial for outpatients with COVID-19 known as ACTIV-2/A5401 to evaluate symptom and SARS-CoV-2 rebound dynamics of the natural course of SARS-CoV-2 infections.

In the randomized, multicenter, placebo-controlled, clinical trial, adult individuals with acute COVID-19 were recruited within seven to ten days of the onset of SARS-CoV-2 infection symptoms. Thereafter, the researchers assessed anti-SARS-CoV-2 therapeutics administered to individuals with mild-to-moderate SARS-CoV-2 infection in outpatient settings.

Nasal swab specimens were obtained daily for SARS-CoV-2 ribonucleic acid (RNA) testing in the first two weeks, and at the end of the third and fourth weeks. The individuals recorded their COVID-19 symptoms daily over four weeks.

Symptom severity was assessed for 13 COVID-19 symptoms including fever, cough, sore throat, fatigue, breathlessness of breathing difficulties, body aches, muscle aches, chills, headaches, nasal congestion or obstruction, nasal discharges, vomiting, diarrhea, and nausea. Symptom rebounds were described as a four-point elevation in the total score for COVID-19 symptoms following improvements after the study began.

SARS-CoV-2 rebound was described as increases of 0.50 log₁₀ RNA copies/mL or greater from the preceding timepoint to viral loads of 3.0 log₁₀ copies/mL or more. High-level SARS-CoV-2 rebound was described as increases exceeding 0.50 log₁₀ RNA copies/mL to viral loads of 5.0 log₁₀ copies/mL or more.

SARS-CoV-2 rebound analyses were limited to individuals recruited between November of 2020 to July of 2021 from placebo treatment groups of phase II-type ACTIV-2/A5401 trials. This included 46 individuals treated with 7,000 mg bamlanivimab, 112 individuals treated with 700 mg bamlanivimab, and 109 individuals treated with the amubarvimab-romlusevimab combination.

In the COVID-19 symptom rebound analyses, 296 individuals were added to the sample population from placebo groups of a phase III clinical trial investigating amubarvimab-romlusevimab combination therapy efficacy.

Phase II clinical trial participants were recruited in the United States, whereas those of amubarvimab-romlusevimab phase III trials were recruited in Argentina, Brazil, South Africa, Mexico, and the U.S. Only individuals with SARS-CoV-2 RNA levels data from three or more time points were included in the SARS-CoV-2 rebound analysis.

Sensitivity analyses were performed considering cases of SARS-CoV-2 rebounds meeting thresholds greater than or equal to four, five, or six log₁₀ RNA copies/mL. For mirroring the five-day nirmatrelvir-ritonavir course, the team performed a secondary analysis limiting COVID-19 symptoms and SARS-CoV-2 RNA assessments before the fifth day.

Study findings

COVID-19 symptom rebounds were detected in 26% of individuals within six days of recruitment and a median of 11 days from the onset of the initial COVID-19 symptoms. Comparatively, SARS-CoV-2 rebounds were identified in 31% of individuals, 13% of which were of high-level.

Of the symptom rebounds, 5% of individuals had symptom rebounds due to hospital admission. Most rebounds were temporary, as 95% and 89% of viral rebounds and symptom rebounds, respectively, were observed at single time points before improvement.

The co-occurrence of symptom rebounds and high-level SARS-CoV-2 rebounds was identified in only 3% of individuals. The median participant age was 49 years, 51% of whom were women and 81% were at elevated risk of severe SARS-CoV-2 infections.

Symptom rebounds among non-hospitalized individuals lasted only for one day among 89% of individuals experiencing COVID-19 symptom rebounds. Symptom rebounds were more frequent among women, individuals at an increased risk of severe COVID-19, those who experienced lower duration since the onset of symptoms, as well as those with greater total scores for COVID-19 symptoms and nasal SARS-CoV-2 RNA levels at baseline.

Evaluating rebounds from the fifth day onward showed that 22% of individuals met the symptom rebound criteria. Furthermore, these symptoms occurred within a median of nine days of recruitment and two weeks from the onset of initial COVID-19 symptoms.

In addition, 3% of individuals experienced rebound COVID-19 symptoms due to hospital admission. In the SARS-CoV-2 rebound analysis, 19%, 13%, and 8% of individuals had SARS-CoV-2 rebounds with rebounding RNA levels of greater than or equal to four, five, and six log₁₀ copies per mL, respectively.

Individuals with SARS-CoV-2 RNA rebound were less likely to be at an increased risk of severe COVID-19 and had greater median nasal swab RNA levels at study initiation. The secondary analysis showed viral rebounds in 20% of individuals

Taken together, 11%, 7%, and 4% of individuals had SARS-CoV-2 rebounds with viral loads greater than or equal to four, five, and six log₁₀ RNA copies/mL, respectively. Assessing rebounds occurring on or after the fifth day indicated that only 1% of individuals met the rebound criteria for symptom rebounds and high-level SARS-CoV-2 rebounds.

Conclusions

Overall, the study findings showed that symptom or viral rebounds were individually common among untreated individuals; however, the co-occurrence of both rebounds was rare. These findings provide valuable insights into the natural course of SARS-CoV-2 infections following nirmatrelvir-ritonavir or other anti-SARS-CoV-2 therapy.