Researchers link immune dysfunction to long COVID, opening door to new treatments

Hours after U.S. Congress members heard pleas from patients and clinicians clamoring for research funding into long COVID, scientists from the University of Zurich released a new study that could explain the mechanism behind the condition—a step towards developing new treatments.

The study, published Jan. 18 in Science, involved 39 healthy controls and 113 COVID-19 patients who were followed for one year. Blood samples from the 40 COVID patients with long COVID contained signs that the complement system, part of the immune system’s first line of defense against pathogens, never turns off after its encounter with the SARS-CoV-2 virus.

“In patients with long COVID, the complement system no longer returns to its basal state, but remains activated and, thus, also damages healthy body cells,” lead author Onur Boyman, M.D., said in a press release. 

Long COVID is officially known as post-acute sequelae of SARS-CoV-2 infection, or PASC. Patients with the condition have at least one new, relapsing or ongoing symptom 30 days or more after coming down with COVID-19. Manifestations of long COVID range from mild to completely debilitating; virtually every organ system can be affected, with a wide range of symptoms spanning from anxiety and exhaustion to shortness of breath, heart problems and even vision loss, according to Yale Medicine.

An October 2023 survey of around 71,000 people by the U.S. Centers for Disease Control estimated that roughly 14% of adults aged 18 and over have ever had long COVID. But given the vast profile of long COVID symptoms and a dearth of reliable biomarkers, those numbers may be unreliable. And regardless, there aren’t dedicated treatments, though drug companies like Laurent Pharmaceuticals are testing therapies in clinical trials.  

The Zurich scientists’ new research suggests a potential direction for new therapies by pointing a finger at excessive complement system activation. To discover this, they profiled nearly 6,600 proteins in the blood of study participants both during their acute infection and again six months later. 

All of the patients with long COVID had markedly elevated blood levels of proteins that facilitate interactions between the complement system and blood clot formation, such as TSP-1 and von Willebrand factor (vWF), compared to healthy controls or COVID patients who didn’t go on to develop long COVID. The long COVID patients also had lower levels of a protein called ADAMTS13, which cleaves vWF and stops the blood clotting process, along with signs of damage to red blood cells, organ tissues and blood vessels. 

Additionally, researchers found evidence that in patients with long COVID, antibodies to Epstein Barr virus and cytomegalovirus might also be driving complement pathway activation. All of the differences between the long COVID patients and other study cohorts were observed both during acute infection and at the six-month mark. 

The findings could explain some of the pathologies seen in earlier studies, such as microclots, by showing how complement system activation drives blood clotting, the researchers said in their study. That said, they acknowledged some caveats: The overall number of participants was relatively low, and there are drawbacks to the high-throughput methods used to identify biomarkers of complement pathway activation.

Still, the results suggest that checking long COVID patients’ hearts early on should be considered, they wrote.

“Moreover, antivirals targeting SARS-CoV-2 or herpesviruses could reduce thromboinflammatory responses,” the researchers added. “Available therapeutics targeting the … complement pathway could offer new treatment strategies for long COVID and possibly other postinfection syndromes.”

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