Could long Covid’s signs of immune dysregulation in the blood lead to a diagnostic test?

Long Covid has long eluded scientists looking for its cause. Not knowing what triggers its persistent and distressing symptoms makes the condition challenging to treat; it’s hard to even say definitively who has it. New research published Thursday in Science has identified proteins present in the blood of people with long Covid that could point the way to a much-needed diagnostic test and possibly to future therapeutic targets.

Scientists at the University of Zurich discovered high levels of proteins involved in the complement system — an important part of the immune system bridging innate and adaptive responses — that were disrupted in people with long Covid symptoms, but not in those who got better after the initial Covid-19 infection or in those who had recovered from long Covid symptoms after six months. The team also found damaged red blood cells and platelets as well as signs of harm to the endothelial cells that line blood vessels.

These biomarkers appeared after the researchers performed high-throughput analyses of more than 6,500 proteins found in the blood serum of 113 people infected with Covid, including 40 people who developed long Covid, and controls who were not infected.

Starting in 2020, a team led by Carlo Cervia-Hasler of University Hospital Zurich and the University of Zurich continued to take samples for a year. Their results were later validated against a larger cohort from Mount Sinai in New York.

Cervia-Hasler told STAT the striking difference in complement proteins was very surprising at first. But then, “it started to make sense because in all these hypotheses that are out there on long Covid, somehow you could connect them a bit with the complement system in the middle. So it will be very interesting further on to see how everything fits under one hat.”

Those hypotheses about the cause of long Covid include the possibility that there are viral reservoirs where SARS-CoV-2 lingers; that inflammation sparked by the infection doesn’t subside; and that the infection triggers autoimmunity, in which the immune system attacks its own cells instead of invaders. Other studies, including one published in November 2023 in Science Translational Medicine, have identified immune signatures in the blood of people with long Covid.

In Thursday’s study, certain complement components went up and down in people with long Covid, changes that could be a clue to why long Covid lingers, Cervia-Hasler said. First there is a cascade of complement proteins in response to the virus. Then complement components subside, leaving the blood and entering healthy cells. The complement system is supposed to fight infected cells and get rid of damaged ones, but when the system is too active, it can also damage healthy cells and renew the battle.

“We could be looking at a vicious cycle,” he said. “After infection or tissue damage where complement is involved, usually it’s not activated anymore after a certain time. The question is, why is it still active in long Covid? Could we block it with certain complement therapy?”

Nadia Roan, a senior investigator at the Gladstone Institute and a professor at University of California, San Francisco, who was not involved with the study, leads a lab that studies immune cells and human viruses, including long Covid. She called the Science study “quite fascinating” in an interview.

“The dysregulation they observed is a bit complex, as some complement components go up and others go down, but overall the results suggest that complement pathways are abnormal in people with long Covid,” said Roan, the senior author of a Nature Immunology paper published earlier in January on immune response in long Covid. “It was also interesting that complement dysregulation seems to normalize in those with long Covid that subsequently recover from the condition.”

The Zurich team’s protein analysis revealed something other researchers have noted: Antibodies against prior herpesvirus infections were reactivated. That finding further supports the idea that people with long Covid are living with immune dysregulation, including increased inflammation, altered autoantibody profiles, and elevated herpesvirus antibody responses, Roan said.

Cervia-Hasler hopes these changes in complement activation could become enough of a long Covid signature in blood samples to develop a diagnostic based on them. Such a test would also look at three other factors: age, body mass index, and signs of abnormal blood clotting with inflammation.

“We really wanted to find something we could use to give patients because many are stigmatized as psychiatric patients who need treatment. Or the care they get, it’s often the wrong one because it’s difficult to objectify what they are reporting,” he said. “And now as Covid tests are even less performed, it’s even more difficult to get a proper diagnosis.”

What’s next? More and larger trials, Cervia-Hesler said, to go into further detail and confirm what they found, looking even longer after the initial Covid-19 infection to understand how it might change over time. And while there are drugs to treat forms of complement dysregulation found in certain genetic diseases, he said much more work needs to be done to establish the mechanism by which the complement system works in long Covid. “Of course, not every Covid patient is the same.”

Gladstone’s Roan takes a similarly cautious view of both treatment and testing. “I think it will be crucial to determine the extent to which dysregulated complement is an actual cause of long Covid, and therefore a potential therapeutic target,” she said. “The extent to which this serves as a useful biomarker of long Covid, however, will require validation in larger cohorts, and it is unlikely that a single biomarker can be used to diagnose long Covid given the heterogeneity of the condition.”

Wolfram Ruf, scientific director of the Center for Thrombosis and Hemostasis at Johannes Gutenberg University in Mainz, Germany, leans more toward a possible diagnostic than a treatment. “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,” he wrote in a related Science commentary.

Cervia-Hesler hopes other research groups will look in more detail at pathways that may have been overlooked. “I look forward also to seeing where the field moves, hopefully toward a diagnostic tool or therapeutic solution as early as possible.”