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Long COVID Linked to Ongoing Immune Activation, Cell Damage in Proteomics Study

Long Covid

NEW YORK – Persistent COVID-19, commonly referred to as "long COVID," involves changes in proteins that can be detected in peripheral blood samples, according to findings from a new proteomic and machine-learning study. The results point to the possibility of unearthing blood-based biomarkers for persistent COVID-19 symptoms.

As they reported in Science on Thursday, the researchers used the SomaLogic SomaScan assay to profile more than 6,500 proteins in 268 blood samples collected over time from 113 individuals with acute COVID-19 infections, including 76 mild and 37 severe COVID-19 cases, as well as from 39 healthy control individuals. One month after the initial infection, 56 individuals experienced Long COVID, and 40 had Long COVID at the six-month mark.

Together with mass spectrometry-based validation and machine-learning analyses, blood serum proteomic profiles at the acute infection and six-month stage from Long COVID cases and from recovered individuals highlighted a role for persistent activation of the innate immune system's complement system in Long COVID.

"During health, the complement system fights infections and removes damaged body cells," first author Carlo Cervia-Hasler, a physician and immunology researcher at the University of Zurich and University Hospital Zurich, explained in an email. "However, if following an infection, the complement system does not return to its basal state but remains activated, it can also damage healthy body cells."

Likewise, the team reported, proteomic shifts found in cases of active Long COVID were consistent with red blood cell damage, blood platelet and blood vessel injury, and other features associated with a process known as thrombo-inflammation, a combination of blood coagulation and inflammatory reactions implicated in conditions ranging from cardiovascular disease or sepsis to trauma.

Based on these results, the researchers reasoned that "early cardiovascular assessment" may benefit patients experiencing Long COVID. In addition, they explained, the complement system and thrombo-inflammation findings point to potential avenues for developing and targeting treatments to tackle the mysterious condition.

"Our discoveries on complement activation fit very well with and may connect previously discussed hypotheses on Long COVID, including viral reservoirs and reactivation, tissue damage, autoimmunity, and persistent inflammation," Cervia-Hasler noted.

Along with the biological clues garnered from the proteomic data, building on biological mechanisms implicated in Long COVID in the past, the latest results also demonstrated the feasibility of coming up with blood-based biomarkers for identifying and potentially diagnosing Long COVID in individuals who experience related symptoms long after the acute infection stage.

"We were able to diagnose Long COVID in patients with active disease six months after initial SARS-CoV-2 infection," Cervia-Hasler said. "Given that Long COVID patients often face psychiatric stigma, an objective blood test is urgently needed to ensure optimal care."

In a related perspectives article in Science, Wolfram Ruf, a researcher affiliated with Johannes Gutenberg University Medical Center Mainz's Center for Thrombosis and Hemostasis and Scripps Research, who was not involved in the study, noted that the proteomic profiles pointed to "localized activation of the innate immune defense complement system as a likely culprit that induces thrombo-inflammation and prevents the restoration of fitness after acute COVID-19."

"Complement and coagulation systems are not only an integral part of the innate immune response but also are connected at several levels in feed-forward amplification loops," Ruf added, suggesting that a "better definition of these interactions in preclinical and clinical settings will be crucial for the translation of new therapeutic concepts in chronic thrombo-inflammatory diseases."