Research Shows Consistent Serum Protein Changes in Long COVID Patients

According to analysis published in Science on Jan. 19, blood samples from patients with long COVID contained significant serum protein changes, which could open the door to the development of biomarker-based tests to identify the condition.

These protein changes “suggest a significant alteration of the complement system, which results in the immune system remaining activated and inflamed after acute infection.” Dysregulation of the complement system – which is responsible for controlling blood clotting and the repair of damaged tissue – “could be behind the wide and varied symptoms experienced by long COVID patients,” the authors of the analysis explained.

Lead researcher Onur Boyman, MD, a professor of immunology at the University of Zurich, explained in a university press release that “the complement system no longer returns to its basal state” in patients with long COVID. Instead, the system “remains activated and, thus, also damages healthy body cells.”

The researchers analyzed blood serum samples from 113 patients. 73 of those patients had fully recovered from COVID-19; 40 had developed long COVID; and 39 were healthy controls. They collected samples at baseline and 6 months after acute illness and searched for serum levels of 6,596 human proteins.

In the blood samples collected at 6 months in the patients who had developed persistent symptoms associated with long COVID, “the blood antimicrobial defense systems of complement and pentraxin 3 were elevated.” They also had “significantly more terminal complement complex (TCC)…which can result in cell activation, breakdown, and tissue damage.” The author specifically wrote that “markers of hemolysis, tissue injury, platelet activation, and monocyte-platelet aggregates were increasing in long COVID,” also highlighting that those patients “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) immunoglobin G (IgG) antibody levels.” These discoveries point toward the possibility that long COVID treatment may be found “in treatments for other chronic diseases involving complement activation, which include neurodegenerative diseases.”

However, other experts emphasize the need for caution, given that the findings need to be replicated with larger studies. For instance, Claire Steves, MBBS, PhD, a professor of aging and health at King’s College London, wrote in an expert reaction both about that concern and the fact that “this study does not have a positive control group—that is, individuals with a non-COVID infection who also had symptoms, so we don’t know if these signals are specific to COVID or related to long symptoms generally.”

Peter Openshaw, MBBS, of Imperial College London, stresses that this research “identifies possible diagnostic markers” that “are not ready to be applied clinically.” He writes that there is hope that this study may point the way forward even though “it would be premature to give new treatments to patients on the basis of these findings.” David Lynn, PhD, a professor of systems immunology at Flinders University in Adelaide, Australia, also said that “much work remains to be done to unify the different mechanisms that have been proposed in these different studies [identifying immune system dysregulation in long COVID] and more importantly to develop novel treatments based on these findings.”

CIDRAP’s website has the news.