Recurrence of Symptoms Following a 2-Day Symptom Free Period in Patients With COVID-19

Recurrence of symptoms after finishing treatment for COVID-19 with nirmatrelvir-ritonavir (Paxlovid) has become increasingly recognized.^1-3 The biological underpinning of this phenomenon is unclear, and its etiology may be multifactorial, including rapid clearance of nirmatrelvir coupled with delayed immune responses or possible development of drug resistance.^1-3 The contribution of treatment to symptom rebound needs to be differentiated from symptom rebound that might occur during the natural history of COVID-19. In this cohort study, we sought to determine how often COVID-19 symptoms recurred when the disease was untreated.

We assessed COVID-19 symptoms for 29 days in untreated participants who received a placebo in the ACTIV-2/A5401 trial between August and November 2020, following Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for cohort studies. ACTIV-2/A5401 (NCT04518410) is a phase 2/3 platform trial to evaluate the safety and efficacy of investigational agents to treat nonhospitalized adults (aged 18 years and older) with COVID-19.⁴ The Advarra institutional review board approved the study; all participants provided written informed consent. Participants had documented SARS-CoV-2 infection and 10 or fewer days experiencing COVID-19 symptoms at study entry.⁴ Participants completed a daily symptom diary from enrollment (day 0) to day 28, which included 13 COVID-19 symptoms, scored by the participant as absent, mild, moderate, or severe (Figure).⁴ We assessed the frequency of targeted symptom recurrence after symptom resolution, defined as all 13 symptoms reported absent for 2 consecutive days.

Among the 158 evaluable participants, 79 (50%) were women, median (IQR) age was 47 years (34-55 years), 28 (18%) self-identified as a minoritized racial group and 48 (31%) as having Hispanic ethnicity. Median (IQR) time from symptom onset to enrollment was 6 days (4-7 days). Sixty-six (42%) reported a high-risk condition, with the highest frequency conditions being hypertension (44 participants [28%]) and obesity (ie, body mass index [calculated as weight in kilograms divided by height in meters squared] greater than 35) (17 participants [11%]).⁴

During 28 days of follow-up, 108 participants (68%) achieved symptom resolution, of which 48 (44%; 30% of the 158 participants) subsequently reported recurrence by the end of the 28 days of follow-up of at least 1 of the 13 targeted symptoms (Table). Among those reporting recurrence of symptoms after reporting resolution of symptoms for 2 consecutive days, 41 participants (85%) reported their symptoms as mild, 7 (15%) reported at least 1 moderate symptom and none reported severe symptoms during recurrence. The most common symptoms reported at time of relapse were cough (21 participants [44%]), fatigue (17 participants [35%]), and headache (17 participants [35%]); these results were similar to symptoms at enrollment, with the exception that body pain and aches were reported more often at enrollment than on recurrence (Table). This profile of symptoms on recurrence was like the profile of persistent symptoms at days 27 and 28 for participants who never resolved all symptoms at end of follow-up (data not shown). Eight hospitalizations (5%) but no deaths occurred among the 158 participants, none occurring among participants who achieved symptom resolution and then experienced recurrence.

Using daily symptoms data from a prospective trial, we found the natural history of untreated COVID-19 was variable and undulating. Over one-third of participants who experienced symptom resolution for at least 2 consecutive days within the first 4 to 5 weeks of COVID-19 symptoms reported recurrent symptoms. Reported symptoms are inherently subjective, and our observed variation may explain some of the rebound of symptoms after treatment for COVID-19, like in cases of what has been described as Paxlovid rebound.^1-3

This study was limited by lack of virologic characterization, including the presence of simultaneous viral rebound. Also, participants were enrolled before COVID-19 vaccinations were available and when the original and Alpha variant SARS-CoV-2 strains circulated, so these results may not be generalizable to the current pandemic, where Omicron variants predominate.⁵ Consistent with an earlier report,⁶ our results in persons with untreated COVID-19 shows that recurring symptoms are common among those who initially improve, but these recrudescent symptoms do not portend progression to severe COVID-19.

Accepted for Publication: September 12, 2022.

Published: October 27, 2022. doi:10.1001/jamanetworkopen.2022.38867

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Smith DM et al. JAMA Network Open.

Corresponding Author: Davey M. Smith, MD, MAS, Department of Medicine, University of California San Diego, School of Medicine, 9500 Gilman Dr, La Jolla, CA 92093-0676 (d13smith@health.ucsd.edu).

Author Contributions: Dr Hughes had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Chew and Hughes contributed equally.

Concept and design: Smith, Li, Moser, Currier, Chew, Hughes.

Acquisition, analysis, or interpretation of data: Smith, Moser, Yeh, Chew, Hughes.

Drafting of the manuscript: Smith, Li, Hughes.

Critical revision of the manuscript for important intellectual content: Smith, Moser, Yeh, Currier, Chew, Hughes.

Statistical analysis: Moser, Yeh, Hughes.

Obtained funding: Smith, Currier, Hughes.

Administrative, technical, or material support: Smith, Chew, Hughes.

Supervision: Smith, Li, Chew, Hughes.

Conflict of Interest Disclosures: Dr Smith reported receiving personal fees from consulting work for Linear Therapies, Model Medicines, Kiadis Pharmaceutical, Bayer Pharmaceuticals, Signant Health, Evidera, Fluxergy, Vx Bioscience, and Pharma Holdings outside the submitted work. Dr Li reported receiving grants from Merck outside the submitted work. Dr Currier reported receiving personal fees for advisory board work from Merck and Company outside the submitted work. Dr Chew reported receiving research funding to her institution from Merck Sharp & Dohme, and reported consulting work for Pardes Biosciences; she reported having a patent pending for ACTIV-2 COVID-19 acute and long-term symptom diaries that will be made available at no cost, as they were developed with federal funding. No other disclosures were reported.

Funding/Support: This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under grant Nos. UM1 AI068634, UM1 AI068636, and UM1 AI106701.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The ACTIV-2/A5401 Study Team members appear in the Supplement.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Additional Contributions: We thank the study participants, site staff, site investigators, and the entire ACTIV-2/A5401 study team; the AIDS Clinical Trials Group, including Joseph J. Eron, MD, University of North Carolina at Chapel Hill School of Medicine, Eric S. Daar, MD, Lundquist Institute at Harbor-UCLA Medical Center, and David A. Wohl, MD, Department of Medicine, University of North Carolina at Chapel Hill School of Medicine; the Harvard Center for Biostatistics in AIDS Research and ACTG Statistical and Data Analysis Center, including Justin Ritz, MS; the National Institute of Allergy and Infectious Diseases/Division of AIDS, including William Erhardt, MD, Arzhang Cyrus Javan, MD, MPH, DTM&H, and Peter Kim, MD, of the National Institutes of Health; the US Government Response to COVID-19; the Foundation for the National Institutes of Health and the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership, including Stacey Adams, PhD; and PPD. All contributors received compensation for activities within ACTIV-2/A5401.