The Evolving Puzzle of Long Covid: What the Latest Research Reveals
Since the initial waves of the Covid-19 pandemic, a significant number of individuals continue to experience persistent symptoms months, even years, after acute infection. This clinical entity, known as Post-Acute Sequelae of Sars-CoV-2 infection (PASC), or long Covid, remains a major public health challenge. Prevalence estimates vary widely, ranging from 3% to over 30% of those infected.
Unraveling the Complexity: Beyond the Initial Infection
Whereas severe cases of Covid-19 have been extensively studied, particularly among hospitalized patients, the biological mechanisms driving long Covid in individuals with mild or moderate initial infections are still poorly understood. Proposed explanations include persistent viral presence, chronic inflammation, immune dysregulation, endothelial dysfunction, microvascular issues, and autoimmune phenomena. But, published results often present contradictions, making it demanding to establish clear links between biological anomalies and clinical symptoms.
The COPER Cohort: A Deep Dive into ‘Mild’ Long Covid
The COPER cohort, a large-scale French study involving the general population, was designed to investigate the connections between persistent long Covid symptoms and blood biomarkers, considering the time elapsed since infection and the clinical heterogeneity of the condition. The study, led by Olivier Robineau, was published in July 2025 in eBiomedecine.
The COPER cohort is nested within the SAPRIS-Sero cohort, which draws participants from three large French population-based cohorts (CONSTANCES, E3N-Générations and NutriNet-Santé). Participants were selected based on serological, virological data, and detailed questionnaires collected between 2020 and 2021.
Between June and November 2022, 1,000 participants were included. After exclusions, the analysis focused on 801 individuals with documented Sars-CoV-2 infection: 490 considered recovered, without persistent symptoms, and 311 experiencing at least one persistent symptom after infection (the PASC group). Importantly, no participant had been hospitalized during the acute phase.
Participants underwent two home visits six months apart, including blood, saliva, and urine samples, along with standardized clinical questionnaires. Fourteen blood biomarkers were analyzed, covering inflammation, immune activation, endothelial activation, and tissue damage.
No Universal Biological Signature for Long Covid
Individuals with long Covid were more likely to be female, had a higher BMI, and were infected earlier in the pandemic than those who recovered fully. The median number of persistent symptoms was three per person, with fatigue, dyspnea (shortness of breath), cough, and sleep disturbances being the most common. Scores for depression, anxiety, fatigue, and cognitive impairment were also significantly higher in the PASC group.
Network analysis of symptoms revealed a weak overall correlation between different symptoms, suggesting they don’t stem from a single mechanism. However, four main symptomatic clusters were identified: a thoracic syndrome, a cognitive syndrome, a general syndrome, and an arthromyalgic syndrome. Interestingly, anosmia (loss of smell) wasn’t associated with other persistent symptoms.
Biologically, no biomarker was significantly associated with overall long Covid status when considering all PASC patients. However, when analyses were stratified by symptom and time since infection, specific associations emerged. In those infected less than a year prior, certain symptoms – particularly anosmia/ageusia (loss of taste) and cough – were linked to markers of immune and viral activation (IFN-γ, IP-10, PD-L1), as well as markers of endothelial activation (ICAM-1, VCAM-1). These associations weakened or disappeared in participants infected for longer than a year.
Follow-up at six months showed that 22% of PASC participants experienced complete symptom resolution, particularly those infected less than a year prior (38% vs 20%). However, changes in biomarkers over time were only weakly correlated with clinical evolution – except for anosmia/ageusia and fatigue, suggesting a closer link between these specific symptoms and underlying biological processes.
Implications for Diagnosis and Treatment
The study authors conclude that long Covid isn’t a homogenous entity, either clinically or biologically. The absence of a global biological signature associated with PASC highlights the limitations of approaches that view long Covid as a disease with a single pathophysiological mechanism.
The observed associations between specific symptoms and biomarkers, primarily within the first year of infection, support dynamic and evolving mechanisms. Persistent immune or viral activation may play a role in early manifestations, while other mechanisms – potentially neurovascular, autoimmune, or functional – may accept over later.
Towards Phenotypic Studies and Personalized Long Covid Care
These findings have significant implications for both translational research and clinical care. “The reported variations in biomarkers from one study to another, which may seem contradictory at first glance, could actually be explained by the heterogeneity of the included populations,” explains Olivier Robineau. “Differences in clinical phenotype (presence or absence of persistent symptoms), time since infection, initial severity, comorbidities, or treatments received can all influence the observed biological profiles.”
“” he continues, “rather than reflecting an inconsistency in the data, these discrepancies could reflect the existence of distinct pathophysiological mechanisms, potentially dependent on time or clinical sub-phenotype. This underscores the need for fine stratification of cohorts in future work, integrating clinical, temporal, and biological variables to identify specific and clinically relevant signatures.”
Clinically, this suggests an individualized approach, considering the patient’s symptom profile and evolutionary context, rather than a uniform interpretation of biomarkers. Strategies should be tailored to symptomatic profiles and time since infection, rather than relying on a uniform approach.
This large-scale study provides essential insights into the complexity of long Covid. It demonstrates that the biological mechanisms associated with persistent symptoms vary depending on the nature of the symptoms and their duration, and no single biomarker can currently define or diagnose PASC.
As long Covid represents a growing burden on healthcare systems, these findings emphasize the need for personalized approaches, both in research and clinical practice, and pave the way for longitudinal studies integrating broader biological analyses to better understand this still largely enigmatic condition.
Reference
- Symptoms and pathophysiology of post-acute sequelae following COVID-19 (PASC): a cohort study. Robineau O. et al. EBioMedicine, Volume 117, 105792
