Changes to Blood Proteins May Offer Further Insights Into Diagnosing Long COVID


A small study offers some more information as to potential biomarkers for the ailment and may provide a better understanding of its path to potential treatments.

The confounding mystery behind what causes Long COVID as well as developing definitive tests to identify and diagnose the condition has been an ongoing frustration for public health officials, clinicians, and patients.

New research, however, looks to shed some light into characteristics of Long COVID. Specifically, blood serum proteins might offer a key to diagnosing Long COVID. A study published in Science showed that patients experiencing Long COVID, “exhibited changes to blood serum proteins indicating activation of the immune system’s complement cascade, altered coagulation, and tissue injury.”

Study Parameters and Findings

This was a multicenter study, which consisted of 39 healthy control patients and 113 COVID-19 patients who were followed-up to 1 year after initial confirmation of infection through PCR test. After confirmation of acute infection, patients were seen for follow-up appointments at 6 months and 12 months to identify biomarkers associated with Long COVID. At the 6-month follow-up, 40 patients had Long COVID symptoms.

The investigators noted that this group that had Long Covid at 6 months showed a higher prevalence of severe acute COVID-19 compared with the 73 other COVID-19 patients.

What You Need to Know

The study suggests that blood serum proteins could serve as key indicators for diagnosing Long COVID.

The research involved a multicenter study with 39 healthy control patients and 113 COVID-19 patients.

The investigators found that active Long COVID is associated with a blood protein signature marked by increased complement activation and thromboinflammation.

Blood serum was collected from both the healthy control cohort and the COVID-19 patient cohort during the acute COVID-19 stage and at 6-month follow-up.

From that, investigators detected differences in serum protein levels from those with severe COVID-19 and those with a milder form. And differences in those with Long COVID and those who did not have it at both the time of acute infection and at the 6 month follow-up.

The investigators noted that in patients who experience severe COVID-19 there can be associations such as autoantibody formation and persistent inflammation after recovery of the acute infection and can confound Long-COVID-associated changes. As such, they searched for differences in the serum.

They found distinctions in the complement system, which is made up of plasma proteins.

“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,” the investigators wrote.

“Our multicenter, longitudinal study provides evidence of an inflammatory signature restricted to patients with active Long COVID, with diagnostic accuracy 6 months after symptom onset and independent of any information on COVID-19 history, thus facilitating clinical applicability,” the investigators wrote.

With the study’s results, they said a cardiovascular assessment of patients with Long COVID might be considered. And in terms of therapeutics, the use of antivirals for COVID-19 and herpesviruses or treatments targeting the terminal complement pathway for Long COVID may be warranted or welcomed considering limitations in this area of clinical care.  


Carlo Cervia-Hasler et al.Persistent complement dysregulation with signs of thromboinflammation in active Long Covid.Science383,eadg7942(2024).DOI:10.1126/science.adg7942

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