Results of the COPER study on long COVID
A national study explores the pathophysiological causes of long COVID
Last updated on 10 June 2025
The essentials
While the long-term consequences of severe COVID-19 are well documented, the mechanisms behind persistent symptoms after a mild form of the disease remain largely unknown. Researchers from the Institut Pierre Louis d’Epidémiologie et de Santé Publique (IPLESP), a Sorbonne University and Inserm research laboratory, in a study coordinated by ANRS Emerging infectious diseases (ANRS MIE), presents the results of the COPER study. This study offers new insight into the links between long-lasting COVID-19 effects (known as PASC – Post-Acute Sequelae of COVID-19- or long COVID) and immuno-inflammatory abnormalities in non-hospitalized patients. The study reveals complex relationships between variations in certain biomarkers, types of persistent symptoms and time since infection. The project has been designated a National Research Priority by the Strategic Orientation Committee on Clinical Trials and Other Research on COVID-19 (CAPNET), and funded by the French Ministry of Health and Prevention and the Ministry of Higher Education, Research and Innovation. This work is published in the journal eBioMedicine , on June 1st2025.
The persistent neurological, cardiovascular and respiratory sequelae of COVID-19, known as PASC (Post-Acute Sequelae of COVID-19), are not limited to severe forms. At the end of 2022, a critical review of the scientific literature highlighted the many hypotheses being explored to explain long COVID: viral persistence, immune dysregulation, chronic inflammation, endothelial dysfunction, coagulation disorders, autoimmunity and mitochondrial damage. While some studies support these hypotheses with biomarkers (IL-6, IFNγ, TNF-α, etc.), numerous methodological limitations have been identified : small numbers, absence of control groups, lack of statistical adjustment, and above all, frequent exclusion of non-hospitalized patients – even though they constitute the majority of cases of PASC.
A large-scale study on long COVID
The COPER study, launched in 2022, hypothesizes that the variability in clinical symptoms can be attributed to several underlying mechanisms. To investigate this hypothesis, a sufficiently large cohort has been assembled to examine symptoms, biomarkers and their evolution over time.
Between June and November 2022, 1,000 participants from general population cohorts (CONSTANCE, E3N-generation, Nutrinet-Santé) were included. A total of 801 participants were included in this initial work, divided into two groups: a group of people fully recovered from SARS-COV-2 infection (n = 490), and a group still suffering from persistent symptoms (n = 311), such as fatigue, shortness of breath, cough or sleep disturbance. No participants were hospitalized. The aim of the study was to better understand the biological mechanisms underlying the persistent symptoms observed after SARS-CoV-2 infection in non-hospitalized patients.
Biological differences in certain symptomatic patients
Biological analyses carried out during two home visits six months apart revealed significant associations between certain blood biomarkers and persistent symptoms, particularly those linked to viral activation, COVID-19 severity and vascular inflammation. However, these abnormalities did not appear to last over time, suggesting the transient nature of certain mechanisms.
One of the conclusions of the study is that analyzing inflammatory markers is probably insufficient to discriminate between people suffering from long COVID. Studies using a similar methodology and taking into account other biomarkers need to be carried out
Conclusion
Beyond the logistical success of implementing such a study – including collaboration between different cohorts, the organization of home visits and the transport of samples from all over France – this first publication from this cohort highlights the clinical and biological heterogeneity of long COVID, as well as the influence of time since infection on the biomarkers analyzed.
It underlines the importance of “multi-omics” studies, i.e. an integrated approach combining several types of data (genomics, transcriptomics, proteomics, metabolomics, etc.) to obtain a global, multidimensional view of the processes potentially involved in post-infectious syndromes. This type of study requires substantial funding. A system of this type and the methodology used could be applied to the study of persistent symptoms occurring after other infections, in the context of epidemics and the emergence of new pathogens spreading through the general population.
The first therapeutic trials were disappointing in terms of medical treatment, perhaps because of the heterogeneity of the patients included. Our study suggests that therapeutic research will have to take into account at least the symptoms and the time since infection to create the most homogeneous study groups possible. We are moving towards personalized or precision medicine.
About ANRS MIE :
ANRS Emerging infectious diseases is an autonomous agency of Inserm (Institut national de la santé et de la recherche médicale). Its mission is to facilitate, evaluate, coordinate and fund research into HIV/AIDS, viral hepatitis, sexually transmitted infections, tuberculosis, and emerging and re-emerging infectious diseases.
For more information: https://www.anrs.fr
About Inserm
Founded in 1964, Inserm (the French National Institute of Health and Medical Research) is a public scientific and technological research organisation dedicated to biomedical research and human health, working throughout the entire process from the laboratory to the patient’s bedside. Internationally, it partners with leading institutions committed to scientific challenges and progress in these fields.
For more information: https://www.inserm.fr/
About Sorbonne University
Sorbonne University is a world-class, multidisciplinary, research-intensive university covering the humanities, health, science and engineering. Anchored in the heart of Paris and with a regional presence, Sorbonne University has 53,000 students, 7,100 teaching and research staff, and over a hundred laboratories. Alongside its partners in the Sorbonne University Alliance, and via its institutes and multidisciplinary initiatives, it conducts and programs research and training activities to strengthen its collective contribution to the challenges of three major transitions: a global approach to health (One Health), resources for a sustainable planet (One Earth), and changing societies, languages and cultures (One Humanity). Sorbonne University is committed to innovation and deeptech with the Cité de l’innovation Sorbonne University, over 15,000 m2 dedicated to innovation, incubation and the link between research and entrepreneurship, as well as the Sorbonne Center of Artificial Intelligence (SCAI), a “house of AI” in the heart of Paris, to organize and give visibility to multidisciplinary AI research. Sorbonne University is also a member of Alliance 4EU+, an innovative model for European universities that develops strategic international partnerships and promotes the openness of its community to the rest of the world.