Fineschi et al. (2026)
- Authors: Serena Fineschi, Joakim Klar, Jens Schuster, Jonas Bergquist, Niklas Dahl
- Institutes: Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden, Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden, The ME/CFS Collaborative Research Centre at Uppsala University, Uppsala, Sweden
- Publisher: Frontiers in Immunology
- Link: DOI
Summary
This research provides evidence of ongoing, systemic immune activation in Long COVID patients nearly three years after their initial infection. By identifying a specific inflammatory signature and ruling out plasma spike protein as the primary driver at this late stage, the study narrows the focus for future diagnostic tests and potential anti-inflammatory treatments. The findings underscore that the physiological disruption in PASC is a long-term, objective biological phenomenon rather than a transient recovery phase.
What was researched?
This study investigated the plasma proteomic profiles of individuals with Post-Acute Sequelae of SARS-CoV-2 infection (PASC) to identify biomarkers of chronic inflammation and immune dysregulation.
Why was it researched?
The researchers sought to understand the biological mechanisms behind the persistent symptoms of Long COVID, particularly whether chronic inflammation continues long after the initial infection. They also aimed to clarify if viral persistence, specifically the presence of spike proteins in the blood, drives this ongoing inflammation.
How was it researched?
The study used proximity extension assay technology to quantify 358 proteins in the plasma of 92 individuals with PASC at an average of 34 months post-infection, comparing them to recovered controls. Researchers also performed gene set enrichment analysis to map immune pathways and measured plasma SARS-CoV-2 spike protein levels using ultra-sensitive assays.
What has been found?
The analysis identified 26 differentially expressed proteins, with Oncostatin M (OSM) and IL-1 receptor antagonist (IL1RN) being the most significantly upregulated. Findings indicated persistent activation of innate and adaptive immune pathways, including TNF-α and IL-6 signaling, while spike protein levels remained indistinguishable from controls. The inflammatory response was consistent across the patient cohort, suggesting no distinct biological subtypes among the participants.
Discussion
The results suggest that PASC is characterized by a stable, low-grade inflammatory state that persists for years independently of detectable viral spike protein in the plasma. This suggests that the immune system may be ‘locked’ in a pro-inflammatory state or responding to different triggers than active viral replication. The identification of OSM and IL1RN as key markers provides new targets for exploring the chronic nature of the condition.
Conclusion & Future Work
The study concludes that PASC involves long-term immune activation and identifies specific protein markers that could serve as diagnostic tools or therapeutic targets. Further research is needed to determine the initial triggers that cause this immune system ‘memory’ of inflammation to persist for years.