Summary: A new study reveals significant findings in the fight against Long Covid. Through a comprehensive analysis of blood serum from 113 patients, researchers discovered changes in blood serum proteins related to the complement system, coagulation, and tissue injury in Long Covid patients.
This indicates an ongoing thromboinflammatory response, a crucial discovery given that about 20% of COVID-19 patients and 5% of all infected individuals develop Long Covid. These findings, which include potential biomarkers and new treatment strategies, provide a promising direction for future diagnostic and therapeutic research.
Long Covid patients show dysregulated activation of the complement system and altered coagulation, suggesting ongoing thromboinflammatory responses.
The study identified potential biomarkers for diagnosing Long Covid.
This research opens new avenues for developing effective treatments for Long Covid.
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.
Persistent complement dysregulation with signs of thromboinflammation in active Long Covid
Acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes various clinical phenotypes, ranging from asymptomatic to life-threatening COVID-19. About 5% of all infected individuals do not recover from acute disease but develop long-term complications, called Long Covid. Current hypotheses on factors contributing to Long Covid include tissue damage, viral reservoirs, autoimmunity, and persistent inflammation. There are currently no diagnostic tests or therapeutic solutions for affected patients.
We followed 39 healthy controls and 113 COVID-19 patients for up to 1 year after initial confirmation of acute SARS-CoV-2 infection to identify biomarkers associated with Long Covid. At 6-month follow-up, 40 patients had Long Covid symptoms. Repeated clinical assessments were paired with blood draws, resulting in a total of 268 longitudinal blood samples. We measured >6500 proteins in serum by proteomics. Top candidate biomarkers were identified using computational tools and further evaluated experimentally.
Long Covid patients exhibited increased complement activation during acute disease, which also persisted at 6-month follow-up. The complement system is part of the innate immune system and contributes to immunity and homeostasis by targeting pathogens and damaged cells, among other functions. Interestingly, blood complement levels normalized in Long Covid patients recovering before their 6-month follow-up. The complement system can be activated by various triggers, resulting in formation of the terminal complement complex (TCC), made of the complement components C5b-9. These complexes can integrate into cell membranes and induce cell activation or lysis.
Long Covid patients showed imbalanced TCC formation, marked by increased soluble C5bC6 complexes and decreased levels of C7-containing TCC formations that can incorporate into cell membranes. This suggested increased membrane insertion of TCCs in Long Covid patients, contributing to tissue damage. Accordingly, Long Covid patients showed elevated tissue injury markers in blood and a thromboinflammatory signature, characterized by markers of endothelial activation, such as von Willebrand factor (vWF), and red blood cell lysis. Low antithrombin III levels in Long Covid patients were accompanied by signs of increased cleavage by thrombin, a driver of TCC formation.
Furthermore, Long Covid patients had elevated platelet activation markers and monocyte–platelet aggregates at 6-month follow-up, particularly in cases where Long Covid persisted for 12 months or more. These patients also showed signs of antibody-mediated activation of the classical complement pathway, which was associated with increased anti-CMV (cytomegalovirus, also known as human herpesvirus 5) and anti-EBV (Epstein-Barr virus) immunoglobulin G (IgG) antibody levels.
Our data suggest that active Long Covid is accompanied by a blood protein signature marked by increased complement activation and thromboinflammation, including activated platelets and markers of red blood cell lysis. Tissue injury may also be complement-mediated and, in turn, activate the complement system. Moreover, complement activation may be driven by antigen–antibody complexes, involving autoantibodies and antibodies against herpesviruses, as well as cross-talk with a dysregulated coagulation system. In addition to offering a basis for new diagnostic solutions, our work provides support for clinical research on complement modulators for patients suffering from Long Covid.