[Skip to Content]

Claim CME

Infectious Diseases

Long-lasting Symptoms After an Acute COVID-19 Infection and Factors Associated With Their Resolution

Educational Objective
To identify the key insights or developments described in this article

1 Credit CME

JAMA Network Open

Published Online: November 9, 2022

Original Investigation

Article Information and Disclosures

Olivier Robineau, MD, PhD^1,2;

Marie Zins, MD, PhD³;

Mathilde Touvier, MD, PhD⁴;

Emmanuel Wiernik, PhD³;

Cedric Lemogne, MD, PhD⁵;

Xavier de Lamballerie, MD, PhD⁶;

Hélène Blanché, PhD⁷;

Jean-François Deleuze, PhD⁷;

Paola Mariela Saba Villarroel, PhD⁶;

Céline Dorival, PhD¹;

Jerome Nicol, PhD¹;

Roselyn Gomes-Rima, MPH⁸;

Emmanuelle Correia, PhD⁸;

Mireille Coeuret-Pellicer, MD, MPH³;

Nathalie Druesne-Pecollo, PhD⁴;

Younes Esseddik, PhD⁴;

Céline Ribet, PhD³;

Marcel Goldberg, MD, PhD³;

Gianluca Severi, PhD^8,9;

Fabrice Carrat, MD, PhD^1,10;

for the Santé, Pratiques, Relations et Inégalités Sociales en Population Générale Pendant la Crise COVID-19–Sérologie (SAPRIS-SERO) Study Group

Author Affiliations

¹Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre-Louis d’Epidémiologie et de Santé Publique, Paris, France
²EA2694, Univ Lille, Centre Hospitalier de Tourcoing, Tourcoing, France
³Population-Based Epidemiological Cohorts, UMS 11, Paris-Saclay University, Versailles St Quentin University, Université de Paris, INSERM, Villejuif, France
⁴Sorbonne Paris Nord University, INSERM U1153, Inrae U1125, Conservatoire National des Arts et Metiers, Nutritional Epidemiology Research Team, Epidemiology and Statistics Research Center–University of Paris, Bobigny, France
⁵Université de Paris, INSERM U1266, Institut de Psychiatrie et Neurosciences de Paris, Paris, France
⁶Unité des Virus Emergents, UVE: Aix Marseille University, IRD 190, INSERM 1207, Institut Hospitalo-Universitaire Méditerranée Infection, Marseille, France
⁷Fondation Jean Dausset–CEPH (Centre d’Etude du Polymorphisme Humain), Paris, France
⁸Centre de recherche Epidémiologique en Santé des Populations UMR1018, Paris-Saclay University, Université de Versailles Saint-Quentin, INSERM, Gustave Roussy, Villejuif, France
⁹Department of Statistics, Computer Science, Applications “G. Parenti,” University of Florence, Florence, Italy
¹⁰Département de santé publique, Hôpital Saint-Antoine, Assistance Publique Hôpitaux de Paris, Paris, France

Santé, Pratiques, Relations et Inégalités Sociales en Population Générale Pendant la Crise COVID-19–Sérologie (SAPRIS-SERO) Study Groupfor the

Read article on JAMA Network

Read Article Claim CME

Key Points

Question What is the duration of persistent symptoms after SARS-CoV-2 infection, and what factors are associated with their resolution?

Findings This cross-sectional study nested in 3 French population-based cohorts found that approximately 10% of individuals with acute COVID-19 infection still had symptoms after 1 year of follow-up. The risk factors associated with the duration of these symptoms vary depending on their persistence.

Meaning This study suggests that persistent symptoms after SARS-CoV-2 infection is a public health concern.

Abstract

Importance Persistent symptoms after SARS-CoV-2 infection are an emerging public health problem. The duration of these symptoms remains poorly documented.

Objective To describe the temporal dynamics of persistent symptoms after SARS-CoV-2 infection and the factors associated with their resolution.

Design, Setting, and Participants This cross-sectional study involved 53 047 participants from 3 French adult population-based cohorts (CONSTANCES [Consultants des Centres d’Examens de Santé], E3N/E4N, and Nutrinet-Santé) who were included in a nationwide survey about SARS-CoV-2 infection. All participants were asked to complete self-administered questionnaires between April 1 and June 30, 2020. Variables included sociodemographic characteristics, comorbid conditions, COVID-19 diagnosis, and acute symptoms. Blood samples were obtained for serologic analysis between May 1 and November 30, 2020, from patients with SARS-CoV-2 infection defined as enzyme-linked immunosorbent assay immunoglobulin G antispike detection confirmed with a neutralization assay. A follow-up internet questionnaire was completed between June 1 and September 30, 2021, with details on persistent symptoms, their duration, and SARS-CoV-2 infection diagnosis by polymerase chain reaction.

Main Outcomes and Measures Persistent symptoms were defined as symptoms occurring during the acute infection and lasting 2 or more months. Survival models for interval-censored data were used to estimate symptom duration from the acute episode. Multivariable adjusted hazard ratios (HRs) were estimated for age, sex, and comorbid conditions. Factors associated with the resolution of symptoms were assessed.

Results A total of 3972 participants (2531 women [63.7%; 95% CI, 62.2%-65.2%]; mean [SD] age, 50.9 [12.7] years) had been infected with SARS-CoV-2. Of these 3972 participants, 2647 (66.6% [95% CI, 65.1%-68.1%]) reported at least 1 symptom during the acute phase. Of these 2647 participants, 861 (32.5% [95% CI, 30.8%-34.3%]) reported at least 1 persistent symptom lasting 2 or more months after the acute phase. After 1 year of follow-up, the estimated proportion of individuals with complete symptom resolution was 89.9% (95% CI, 88.7%-90.9%) with acute symptoms. Older age (>60 years; HR, 0.78; 95% CI, 0.68-0.90), female sex (HR, 0.64; 95% CI, 0.58-0.70), history of cancer (HR, 0.61; 95% CI, 0.47-0.79), history of tobacco consumption (HR, 0.80; 95% CI, 0.73-0.88), high body mass index (≥30: HR, 0.75; 95% CI, 0.63-0.89), and high number of symptoms during the acute phase (>4; HR, 0.43; 95% CI, 0.39-0.48) were associated with a slower resolution of symptoms.

Conclusions and Relevance In this cross-sectional study, persistent symptoms were still present in 10.1% of infected individuals at 1 year after SARS-CoV-2 infection. Given the high level of cumulative incidence of COVID-19, the absolute prevalent number of people with persistent symptoms is a public health concern.

Claim CME

Sign in to take quiz and track your certificates

Buy This Activity

Article Information

Accepted for Publication: September 8, 2022.

Published: November 9, 2022. doi:10.1001/jamanetworkopen.2022.40985

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

Corresponding Author: Olivier Robineau, MD, PhD, Centre Hospitalier Gustave Dron, Rue du président René Coty, 59200 Tourcoing, France (olivier.robineau@univ-lille.fr).

Author Contributions: Drs Robineau and Carrat had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Robineau, Touvier, Nicol, Severi, Carrat.

Acquisition, analysis, or interpretation of data: Robineau, Zins, Touvier, Wiernik, Lemogne, de Lamballerie, Blanché, Deleuze, Saba Villarroel, Dorival, Gomes-Rima, Correia, Coeuret-Pellicer, Druesne-Pecollo, Esseddik, Ribet, Goldberg, Severi, Carrat.

Drafting of the manuscript: Robineau, Gomes-Rima, Carrat.

Critical revision of the manuscript for important intellectual content: Robineau, Zins, Touvier, Wiernik, Lemogne, de Lamballerie, Blanché, Deleuze, Saba Villarroel, Dorival, Nicol, Correia, Coeuret-Pellicer, Druesne-Pecollo, Esseddik, Ribet, Goldberg, Severi.

Statistical analysis: Robineau.

Obtained funding: Zins, Touvier, Dorival, Goldberg, Carrat.

Administrative, technical, or material support: Touvier, Blanché, Deleuze, Saba Villarroel, Dorival, Nicol, Correia, Coeuret-Pellicer, Druesne-Pecollo, Esseddik, Goldberg, Severi.

Supervision: Robineau, Nicol, Druesne-Pecollo, Esseddik, Carrat.

Conflict of Interest Disclosures: Dr Robineau reported receiving personal fees and nonfinancial support from Gilead, MSD, and ViiV outside the submitted work. Dr Lemogne reported receiving personal fees and nonfinancial support from Lundbeck and Otsuka Pharmaceutical outside the submitted work. Dr de Lamballerie reported receiving grants from the French Ministry of Research during the conduct of the study. Dr Carrat reported receiving grants from Agence Nationale de la Recherche, Fondation pour la Recherche Médicale, and INSERM during the conduct of the study and personal fees from Sanofi outside the submitted work. No other disclosures were reported.

Funding/Support: The Santé, Pratiques, Relations et Inégalités Sociales en Population Générale Pendant la Crise COVID-19–Sérologie (SAPRIS-SERO) was supported by grants ANR-20-COVI-000 and ANR-10-COHO-06 from ANR (Agence Nationale de la Recherche), grant 20RR052-00 from Fondation pour la Recherche Médicale, and grant C20-26 from Institut National de la Santé et de la Recherche Médicale (INSERM).

Role of the Funder/Sponsor: The funding sources 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 SAPRIS-SERO Study Group members are listed in Supplement 2.

References

World Health Organization. Coronavirus disease (COVID-19): post COVID-19 condition. Accessed April 12, 2022. https://www.who.int/news-room/questions-and-answers/item/coronavirus-disease-(covid-19)-post-covid-19-condition

Hirschenberger M , Hunszinger V , Sparrer KMJ . Implications of innate immunity in post-acute sequelae of non-persistent viral infections. Cells. 2021;10(8):2134. doi:10.3390/cells10082134 PubMed Google Scholar Crossref

Matta J , Wiernik E , Robineau O , et al; Santé, Pratiques, Relations et Inégalités Sociales en Population Générale Pendant la Crise COVID-19–Sérologie (SAPRIS-SERO) Study Group. Association of self-reported COVID-19 infection and SARS-CoV-2 serology test results with persistent physical symptoms among French adults during the COVID-19 pandemic. JAMA Intern Med. 2022;182(1):19-25. doi:10.1001/jamainternmed.2021.6454 PubMed Google Scholar Crossref

Sudre CH , Murray B , Varsavsky T , et al. Attributes and predictors of long COVID. Nat Med. 2021;27(4):626-631. doi:10.1038/s41591-021-01292-y PubMed Google Scholar Crossref

Ghosn J , Piroth L , Epaulard O , et al; French COVID Cohort Study and Investigators Groups. Persistent COVID-19 symptoms are highly prevalent 6 months after hospitalization: results from a large prospective cohort. Clin Microbiol Infect. 2021;27(7):1041.e1-1041.e4. doi:10.1016/j.cmi.2021.03.012 PubMed Google Scholar Crossref

Robineau O , Wiernik E , Lemogne C , et al. Persistent symptoms after the first wave of COVID-19 in relation to SARS-CoV-2 serology and experience of acute symptoms: a nested survey in a population-based cohort. Lancet Reg Health Eur. 2022;17:100363. doi:10.1016/j.lanepe.2022.100363 PubMed Google Scholar Crossref

Whitaker M , Elliott J , Chadeau-Hyam M , et al. Persistent COVID-19 symptoms in a community study of 606,434 people in England. Nat Commun. 2022;13(1):1957. doi:10.1038/s41467-022-29521-z PubMed Google Scholar Crossref

Carrat F , de Lamballerie X , Rahib D , et al; for the SAPRIS and SAPRIS-SERO study groups. Antibody status and cumulative incidence of SARS-CoV-2 infection among adults in three regions of France following the first lockdown and associated risk factors: a multicohort study. Int J Epidemiol. 2021;50(5):1458-1472. doi:10.1093/ije/dyab110 PubMed Google Scholar Crossref

Soriano JB , Murthy S , Marshall JC , Relan P , Diaz JV ; WHO Clinical Case Definition Working Group on Post-COVID-19 Condition. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022;22(4):e102-e107. doi:10.1016/S1473-3099(21)00703-9 PubMed Google Scholar Crossref

Turnbull BW . The empirical distribution function with arbitrarily grouped, censored and truncated data. J R Stat Soc B. 1976;38(3):290-295. doi:10.1111/j.2517-6161.1976.tb01597.x Google Scholar Crossref

Anderson-Bergman C . icenReg: regression models for interval censored data in R. J Stat Softw. 2017;81:1-23. doi:10.18637/jss.v081.i12 Google Scholar Crossref

R Development Core Team. R: a language and environment for statistical computing. 2012. Accessed January 20, 2021. http://www.R-project.org

Nehme M , Braillard O , Alcoba G , et al; COVICARE TEAM. COVID-19 symptoms: longitudinal evolution and persistence in outpatient settings. Ann Intern Med. 2021;174(5):723-725. doi:10.7326/M20-5926 PubMed Google Scholar Crossref

Davis HE , Assaf GS , McCorkell L , et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021;38:101019. doi:10.1016/j.eclinm.2021.101019 PubMed Google Scholar Crossref

Tran VT , Porcher R , Pane I , Ravaud P . Course of post COVID-19 disease symptoms over time in the ComPaRe long COVID prospective e-cohort. Nat Commun. 2022;13(1):1812. doi:10.1038/s41467-022-29513-z PubMed Google Scholar Crossref

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 CME points in the American Board of Surgery’s (ABS) Continuing Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.