Thursday, August 04, 2022

Preprint: Viral and Symptom Rebound in Untreated COVID-19 Infection

Credit NIAID



For the past several months we've seen anecdotal reports of patients receiving Paxlovid whose symptoms (and sometimes positive PCR test results) returned after ending the treatment. 

Last May, the CDC released a HAN Advisory (see COVID-19 Rebound After Paxlovid Treatment) on the phenomenon - and as of yesterday President Biden was reportedly in his 5th day of `rebound'. 

But even in that May HAN Advisory, the CDC cautioned that COVID rebound could occur even in patients not taking Paxlovid, and suggested it might even be common in COVID patients, stating:

A brief return of symptoms may be part of the natural history of SARS-CoV-2 (the virus that causes COVID-19) infection in some persons, independent of treatment with Paxlovid and regardless of vaccination status.

All of which brings us to a preprint, published this week, which finds that COVID rebound may be common, even among patients who were receiving no antiviral treatments. 

Viral and Symptom Rebound in Untreated COVID-19 Infection

Rinki Deo, Manish C Choudhary, Carlee Moser, Justin Ritz, Eric S Daar, David A Wohl, Alexander L Greninger, Joseph J Eron, Judith S Currier, Michael D Hughes, Davey M Smith, Kara W Chew, Jonathan Z Li



There are reports of viral RNA and symptom rebound in people with COVID-19 treated with nirmatrelvir/ritonavir. Since the natural course of viral and symptom trajectories of COVID-19 has not been well described, we evaluated the incidence of viral and symptom rebound in untreated outpatients with mild-moderate COVID-19. 


The study population included 568 participants enrolled in the ACTIV-2/A5401 platform trial who received placebo. Anterior nasal swabs were collected for SARS-CoV-2 RNA testing on days 0-14, 21 and 28. Participants recorded the severity of 13 targeted symptoms daily from day 0 to 28. 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. Baseline was defined as study day 4 (primary analysis) or 8 days from symptom onset (secondary analysis). 


In both the primary and secondary analyses, 12% of participants had viral rebound. Viral rebounders were older than non-rebounders (median 54 vs 47 years, P=0.04). Symptom rebound occurred in 27% of participants after initial symptom improvement and in 10% of participants after initial symptom resolution. The combination of high-level viral rebound to ≥5.0 log10 RNA copies/mL and symptom rebound 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. 


This study was supported by the National Institute of Allergy and Infectious Diseases; ACTIV-2/A5401 number NCT04518410.

Regardless of the circumstances, the CDC has this advice for anyone experiencing COVID rebound:

Recommendations for the Public
  • You may be experiencing COVID-19 rebound if you have been diagnosed in the past 2 weeks and have recovered from COVID-19 and then experience recurrent COVID-19 symptoms or develop newly positive test results after recovery.
  • If you experience COVID-19 rebound, you should follow CDC’s isolation guidance. Isolate again and restart the recommended 5-day isolation period at the time of recurrence of symptoms or a new positive COVID-19 test result. You can end re-isolation after 5 days if you are fever-free for 24 hours without the use of fever-reducing medication and your symptoms are improving. You should also wear a mask for 10 days after rebound.
  • Contact a healthcare provider if your COVID-19 rebound symptoms persist or worsen.
  • Consult with your healthcare provider if you have additional questions about your treatment.
  • You are encouraged to report a possible case of COVID-19 rebound after Paxlovid treatment to Pfizer using the following online tool: Pfizer Safety Reportingexternal icon.