Analysis of blood samples from patients with Long-COVID – a debilitating condition with unknown causes – has revealed serum protein changes as the likely culprit. The findings highlight potential biomarkers for Long-COVID diagnosis and could yield insights into treating the condition. Not everyone fully recovers from COVID-19. Roughly 20% of patients diagnosed with it and about 5% of all SARS-CoV-2–infected persons develop lingering symptoms, called Long-COVID, that can persist for many months.

Symptoms of Long-COVID can include fatigue, post-exertional malaise, and cognitive impairment, and involve multiple organs. Although previous studies have shown that patients with Long-COVID display signs of immune dysfunction, persistent immune cell activation, and autoimmune antibody production, the root cause of Long-COVID is poorly understood, and diagnostic biomarkers for the condition aren’t well defined.

Currently, Long-COVID also lacks an effective treatment. In a new study, Carlo Cervia-Hasler and colleagues report the findings of a longitudinal analysis of blood serum from 113 patients who either fully recovered from COVID-19 or developed Long-COVID, as well as healthy controls. Using high-throughput proteomics approaches, Cervia-Hasler et al. measured serum levels of 6596 human proteins across study participants. Those with confirmed acute COVID-19 were followed for up to a year, and their blood serum was sampled again at 6 months and at 12 months where possible. Patients experiencing Long-COVID exhibited changes to blood serum proteins, indicating dysregulated activation of the complement system, altered coagulation, and tissue injury, suggesting ongoing thromboinflammatory responses.

The authors show that, at the cellular level, the thromboinflammatory signature associated with Long-COVID was linked with increased monocyte-platelet aggregates. Dysregulation of complement proteins could contribute to the thromboinflammation associated with Long-COVID. The findings of the study identify potential biomarkers for Long Covid and new treatment strategies that warrant further diagnostic and therapeutic investigation.

“Although therapeutic interventions with coagulation and complement inhibitors in acute COVID-19 produced mixed results, the pathological features specific for Long-COVID suggest potential interventions for clinical testing,” writes Wolfram Ruf in a related Perspective.