For many people, covid is an illness that blusters in and out of our lives as cases spike and recede. But for tens of millions of others, a case of covid is the beginning of a chronic and sometimes debilitating illness that persists for months or even years.  What makes individuals with long covid different from those who get infected and recover? According to a new paper, an often overlooked part of the immune system is unusually active in these people.

A team of researchers from Switzerland compared protein levels in blood samples taken from patients who had never had covid, those who had recovered from covid, and those who had developed long covid. “We wanted to understand what drives long covid, what keeps long covid active,” says Onur Boyman, an immunologist at the University of Zurich and an author of the study.

The scientists found that people with long covid exhibit changes in a suite of proteins involved in the complement system, which helps the immune system destroy microbes and clear away cellular debris. The results echo what at least one other group has found. 

None of the existing research proves that these changes drive the disease. But they offer up a new avenue for treatment exploration by helping doctors pick the best people to trial certain drugs “There aren’t really any effective therapies,” says Aran Singanayagam, a respiratory medicine specialist who studies lung infections at Imperial College London. “So we are quite desperate, and it’s a big problem.” 

The researchers began by looking at levels of more than 6,500 proteins in the blood of 113 people who tested positive for SARS-CoV-2 and 39 people who had never been infected. Six months later, they took new blood samples. By that time, 73 people who had been infected had recovered, and 40 had gone on to develop long covid. Many of the proteins elevated in people with long covid were also elevated in people who had recovered from severe covid. But the markers that were unique to the long covid groups pointed to abnormal activation of the complement system.

What is the complement system? Good question. “We never hear of it as non-immunologists,” Boyman says. But it plays a vital role in defending the body against microorganisms. The complement system is composed of more than 30 proteins produced by the liver that travel the bloodstream and act as an immune surveillance system. Activation of the complement system kicks off a cascade of reactions that recruits immune cells to the site of an infection, flags pathogens for destruction, or even destroys microbes by poking holes in them. The system, as its name suggests, complements the activity of antibodies. But when it goes awry, it can cause widespread inflammation and damage cells and blood vessels

When the results pointed to abnormal activation of the complement system as a distinguishing feature of long covid, “we all of a sudden said ‘Oh, this makes so much sense,’” Boyman says. “The complement system is so central, not only communicating with the immune system but also communicating with the blood clotting system—with the endothelial cells, with platelets, with red blood cells, and going into all the organs.” That might explain why some researchers have found tiny clots in people with the disease.

Why the complement system might go awry after a covid infection isn’t clear. “To me, when you see complement activation like this, it suggests that you have ongoing infection,” says Timothy Henrich, an immunologist at the University of California, San Francisco. That residual virus could keep the complement system active. Or it’s possible that lingering tissue damage keeps the system engaged. Or maybe it’s something else entirely. “The fundamental issue that we have with long covid research right now is that we have a lot of associations, but we don’t have a lot of causations that have been proven,” Henrich says. 

This isn’t the only paper to point to complement dysregulation as a feature of long covid. Back in October Paul Morgan, an immunologist at the Cardiff University School of Medicine, and his colleagues posted research—not yet peer-reviewed—that also found abnormal complement protein levels in people with long covid. Their group wasn’t able to follow patients over time, from acute covid through to the development of long covid. Both groups identified a set of markers that seem predictive of long covid, although not the same markers. Singanayagam is skeptical that any of these markers could offer a definitive diagnosis. 

But if the complement system is to blame for some of the symptoms of long covid, there might be a solution. Companies already have drugs to block the system’s activation. They’re approved to treat some rare genetic and autoimmune diseases. Some of those therapies have already been tested in people with severe covid, with mixed results. But that could be because researchers didn’t have a way of including only those people with signs of complement dysregulation, Morgan says. If a company launched a trial of these therapies in people with long covid, it could use some of these markers to enroll the people who might benefit most. “Treating with anti-complement drugs might actually give us, for really the first time, an effective therapy for long covid,” he says. Morgan’s team has already started talking to companies that have developed these therapies.

But even if these drugs work—and that’s still a big “if”—they’re not likely to work for everyone. Long covid is “such a heterogeneous collection of conditions,” says Singanayagam. “It’s brain fog, fatigue, chest pain—and different patients have different degrees of each of those.” In Morgan’s study, only about a third to half of long covid patients had clear and obvious complement dysregulation. 

Henrich says the paper provides important insights. But the mystery of what drives long covid is far from solved. “This is a 1,000-piece jigsaw puzzle and you finished an edge,” he says. “That’s a good start, but it’s not the entire puzzle.”