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. 2025 Jul:117:105792.
doi: 10.1016/j.ebiom.2025.105792. Epub 2025 May 30.

Symptoms and pathophysiology of post-acute sequelae following COVID-19 (PASC): a cohort study

Olivier Robineau  1 , Sophie Hüe  2 , Mathieu Surenaud  2 , Cédric Lemogne  3 , Céline Dorival  4 , Emmanuel Wiernik  5 , Sebastien Brami  2 , Jerome Nicol  4 , Xavier de Lamballerie  6 , Hélène Blanché  7 , Jean-François Deleuze  7 , Céline Ribet  5 , Marcel Goldberg  5 , Gianluca Severi  8 , Mathilde Touvier  9 , Marie Zins  5 , Yves Levy  10 , Jean-Daniel Lelievre  10 , Fabrice Carrat  11
Affiliations

Symptoms and pathophysiology of post-acute sequelae following COVID-19 (PASC): a cohort study

Olivier Robineau et al. EBioMedicine. 2025 Jul.

Abstract

Background: Several studies reported long-term consequences of severe COVID-19. However, pathophysiological mechanisms of Post-Acute Sequelae following COVID-19 (PASC) in patients with mild acute COVID-19 have been less investigated. Specifically, the link between PASC and immuno-inflammatory abnormalities is inconsistent in the literature. The hypothesis that different pathophysiological mechanisms could explain the persistent symptoms needs to be explored.

Methods: The COPER cohort is a prospective study that included participants with PASC and with a history of COVID-19 without persistent symptoms. None were hospitalised for COVID-19. Participants underwent two home visits six months apart for biological sample collection and completed questionnaires on medical history, infection, vaccination, symptoms, and mental health. The study analysed association between persistent symptoms and 14 blood biomarkers, comparing participants with PASC with recovered participants.

Findings: Between June and November 2022, 1000 participants were included in the study, 199 were excluded due to missing data or sample (35), SARS-CoV-2 infection less than 3 months (36) or lack of known SARS-CoV-2 infection and negative serology (128), with two groups analysed: recovered (n = 490), PASC (n = 311). Participants with PASC were more frequently women, had a higher BMI and a median number of 3 persistent symptoms, with common symptoms being asthenia, dyspnoea, cough, and sleep disorders. Biological analysis revealed significant associations between certain PACS symptoms and biomarkers of viral activation (IFNγ, IP-10), COVID-19 severity (CD163) and vascular activation (VCAM-1, ICAM-1), mainly in subjects whose symptoms had lasted less than a year. However, these associations did not persist over time.

Interpretation: The results suggest a polymorphic and dynamic pathophysiology according to symptoms and time since infection. Other hypotheses, beyond those related to persistent inflammation, should be explored.

Funding: French Ministry of Health and Prevention and the French Ministry of Higher Education, Research and Innovation.

Keywords: Biomarkers; Long COVID; PASC; Post-infectious symptoms; Postacute symptoms following COVID-19; SARS-CoV-2.

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Conflict of interest statement

Declaration of interests OR declare financial support from Gilead, ViiV, MSD, Moderna, Pfizer outside the submitted work. CL reports non-financial support from Nordic Pharma France, outside the submitted work. Other authors have nothing to declare.

Figures

Fig. 1
Fig. 1
Flow chart of the COPER survey. ∗Defined by the absence of symptoms but a history of positive serology and/or a positive PCR test; ∗∗defined by the absence of SARS-CoV-2 infection by RT-PCR and the absence of positive serological test made on serum taken at the inclusion visit (M0).
Fig. 2
Fig. 2
Network analysis of persistent symptoms in participants with PASC. The thickness of the link indicates the strength of the association. Symptoms involved in syndrome are coloured. comp: complaints; dis: disorder, art: articular.
Fig. 3
Fig. 3
Resolution of symptoms between M0 and M6 among the participants with PASC. A) Overall PASC; B) PASC infected less than one year before M0; C) PASC infected more than one year before M0. Proportion of persistent symptoms at M6 are shown in percentage. comp: complaints; dis: disorder.
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