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

Abstract

Background: Many patients report persistent symptoms after COVID-19. Our aim was to determine whether some of these symptoms were more associated with past SARS-CoV-2 infection compared to other conditions.

Methods: This prospective survey was nested in CONSTANCES, a randomly selected French population-based cohort, started in 2012. All participants being followed-up by internet completed 2 questionnaires during the first wave of the pandemic focusing on the acute symptoms of their COVID-19-like illness. Serological tests for SARS-CoV-2 were then performed (May-Nov 2020). Between December 2020 and January 2021, participants completed a third questionnaire about symptoms that had lasted more than 2 months. Participants were classified into four groups according to both European Center for Diseases Control (ECDC) criteria for COVID-19 (ECDC+ or ECDC-) and serological SARS-CoV-2 test results (Sero+ or Sero-). To compare the risk of each persistent symptom among the groups, logistic regression models were adjusted for age, sex, educational level, comorbidities, and the number of acute symptoms declared during the first wave of the epidemic. A mediation analysis was performed to estimate the direct effect of the infection on persistent symptoms and its indirect effect via the initial clinical presentation.

Findings: The analysis was performed in 25,910 participants. There was a higher risk of persistent dysgeusia/anosmia, dyspnea and asthenia in the ECDC+/Sero+ group than in the ECDC+/Sero- group (OR: 6.83 [4.47-10.42], 1.69 [1.07-2.6] and 1.48 [1.05-2.07], respectively). Abdominal pain, sensory symptoms or sleep disorders were at lower risk in the ECDC+/Sero+ group than in the ECDC+/Sero- group (0.51 [0.24-0.96], 0.40 [0.16-0.85], and 0.69 [0.49-0.95], respectively). The mediation analysis revealed that the association of the serological test results with each symptom was mainly mediated by ECDC symptoms (proportion mediated range 50-107%).

Conclusion: A greater risk of persistent dysgeusia/anosmia, dyspnea and asthenia was observed in SARS-CoV-2 infected people. The initial clinical presentation substantially drives the association of positive serological test results with persistent symptoms.

Funding: French National Research Agency.

Keywords: COVID-19; Constances; Long-covid; Persistent symptoms; Populationbased study; Post-covid condition; Post-infectious symptoms.

Figure 1

Concept and design of the mediation analysis for the association of SARS-COV-2 infection with persistent symptoms. (1) Total effect model (2) Basic mediation model (3) Full mediation model used in the study. The mediation analysis allows us to evaluate the part of the direct and indirect effect (2) in the total effect (1). The full model (3) took also into account the interaction between the exposure and the mediator (b and d) and was adjusted on confounding factors. We calculated the total effect (TE= a+b+c+d), the direct effect of the exposure (a+b: natural direct effect, NDE) and the indirect effect mediated by the ECDC symptoms (c+d: natural indirect effect, NIE). The proportion mediated is represented by NIE/TE. The proportion due to interaction is NDE/TE.