Are the belief in having had COVID-19 infection and actually having had the infection as verified by SARS-CoV-2 serology testing associated with persistent physical symptoms during the COVID-19 pandemic?
In this cross-sectional analysis of 26 823 adults from the population-based French CONSTANCES cohort during the COVID-19 pandemic, self-reported COVID-19 infection was associated with most persistent physical symptoms, whereas laboratory-confirmed COVID-19 infection was associated only with anosmia. Those associations were independent from self-rated health or depressive symptoms.
Findings suggest that persistent physical symptoms after COVID-19 infection should not be automatically ascribed to SARS-CoV-2; a complete medical evaluation may be needed to prevent erroneously attributing symptoms to the virus.
After an infection by SARS-CoV-2, many patients present with persistent physical symptoms that may impair their quality of life. Beliefs regarding the causes of these symptoms may influence their perception and promote maladaptive health behaviors.
To examine the associations of self-reported COVID-19 infection and SARS-CoV-2 serology test results with persistent physical symptoms (eg, fatigue, breathlessness, or impaired attention) in the general population during the COVID-19 pandemic.
Design, Setting, and Participants
Participants in this cross-sectional analysis were 26 823 individuals from the French population-based CONSTANCES cohort, included between 2012 and 2019, who took part in the nested SAPRIS and SAPRIS-SERO surveys. Between May and November 2020, an enzyme-linked immunosorbent assay was used to detect anti–SARS-CoV-2 antibodies. Between December 2020 and January 2021, the participants reported whether they believed they had experienced COVID-19 infection and had physical symptoms during the previous 4 weeks that had persisted for at least 8 weeks. Participants who reported having an initial COVID-19 infection only after completing the serology test were excluded.
Main Outcomes and Measures
Logistic regressions for each persistent symptom as the outcome were computed in models including both self-reported COVID-19 infection and serology test results and adjusting for age, sex, income, and educational level.
Of 35 852 volunteers invited to participate in the study, 26 823 (74.8%) with complete data for serologic testing and self-reported infection were included in the present study (mean [SD] age, 49.4 [12.9] years; 13 731 women [51.2%]). Self-reported infection was positively associated with persistent physical symptoms, with odds ratios ranging from 1.44 (95% CI, 1.08-1.90) to 16.61 (95% CI, 10.30-26.77) except for hearing impairment (odds ratio, 1.38; 95% CI, 0.76-2.51), joint pain (odds ratio, 1.32; 95% CI, 0.98-1.80) and sleep problems (odds ratio, 1.12; 95% CI, 0.87-1.44). A serology test result positive for SARS-COV-2 was positively associated only with persistent anosmia (odds ratio, 2.59; 95% CI, 1.57-4.28), even when restricting the analyses to participants who attributed their symptoms to COVID-19 infection. Further adjusting for self-rated health or depressive symptoms yielded similar results. There was no significant interaction between belief and serology test results.
Conclusions and Relevance
The findings of this cross-sectional analysis of a large, population-based French cohort suggest that persistent physical symptoms after COVID-19 infection may be associated more with the belief in having been infected with SARS-CoV-2 than with having laboratory-confirmed COVID-19 infection. Further research in this area should consider underlying mechanisms that may not be specific to the SARS-CoV-2 virus. A medical evaluation of these patients may be needed to prevent symptoms due to another disease being erroneously attributed to “long COVID.”
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Accepted for Publication: September 17, 2021.
Published Online: November 8, 2021. doi:10.1001/jamainternmed.2021.6454
Correction: This article was corrected on March 21, 2022, to fix errors in the article and Supplement 1.
Corresponding Author: Cédric Lemogne, MD, PhD, Service de Psychiatrie de l’adulte, Hôpital Hôtel-Dieu, 1 place du Parvis Notre-Dame, 75004 Paris, France (email@example.com).
Author Contributions: Drs Matta and Lemogne 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.
Acquisition, analysis, or interpretation of data: Matta, Wiernik, Robineau, Carrat, Touvier, de Lamballerie, Blanché, Deleuze, Hoertel, Ranque, Goldberg, Lemogne.
Drafting of the manuscript: Matta, Lemogne.
Critical revision of the manuscript for important intellectual content: Matta, Wiernik, Robineau, Carrat, Touvier, Severi, de Lamballerie, Blanché, Deleuze, Gouraud, Hoertel, Ranque, Goldberg, Zins.
Statistical analysis: Matta, Robineau, Hoertel.
Obtained funding: Blanché, Zins.
Administrative, technical, or material support: Blanché, Deleuze, Gouraud, Goldberg, Zins.
Supervision: Carrat, Touvier, Blanché, Gouraud, Goldberg, Lemogne.
Conflict of Interest Disclosures: Dr Robineau reported personal fees and nonfinancial support from Gilead, ViiV Healthcare, and Merck Sharp & Dohme Corp outside the submitted work. Dr Carrat reported personal fees from Sanofi outside the submitted work. Dr de Lamballerie reported grants from the French Ministry of Research and the French Institute of Health and Medical Research during the conduct of the study. Dr Hoertel reported personal fees and nonfinancial support from Lundbeck outside the submitted work. Dr Lemogne reported personal fees from Boehringer Ingelheim, Janssen-Cilag, Lundbeck, and Otsuka Pharmaceutical outside the submitted work. No other disclosures were reported.
Funding/Support: The CONSTANCES cohort benefits from grant ANR-11-INBS-0002 from the French National Research Agency. CONSTANCES is supported by the Caisse Nationale d’Assurance Maladie, the French Ministry of Health, the Ministry of Research, and the Institut National de la Santé et de la Recherche Médicale (INSERM). CONSTANCES is also partly funded by AstraZeneca, Lundbeck, L’Oréal, and Merck Sharp & Dohme Corp. The Santé, Pratiques, Relations et Inégalités Socials en Population Générale Pendant la Crise COVID-19 (SAPRIS) and SAPRIS-Sérologie (SERO) study was supported by grants ANR-10-COHO-06 and ANR-20-COVI-000 from the Agence Nationale de la Recherche; grant 20DMIA014-0 from Santé Publique France; grant 20RR052-00 from the Fondation pour la Recherche Médicale; and grant C20-26 from INSERM.
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: A complete list of the members of the SAPRIS-SERO study group appears in Supplement 2.
Additional Contributions: Céline Ribet, PhD, Mireille Pellicer, MD, Laura Quintin, MSc, Stephane Le Got, MSc, all from the CONSTANCES cohort, and Céline Dorival, PhD, and Jerôme Nicol, MSc, from INSERM Institut Pierre Louis d’Epidémiologie et de Santé Publique, substantially contributed to data collection for this work.
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