Study identifies potential biomarker to detect long Covid

New research indicates that people with this condition have a dysregulated complement system. The discovery opens the door to drug development and diagnostic tests

A nurse examines respiratory parameters of a woman in a rehabilitation clinic for long Covid patients in Germany.
A nurse examines respiratory parameters of a woman in a rehabilitation clinic for long Covid patients in Germany.picture alliance (dpa/picture alliance via Getty I)
Jessica Mouzo

Four years are about to pass since the outbreak of a pandemic that shook the world and although the Covid virus is now under control, its hangover still weighs on millions of people. Long Covid — which is associated with more than 200 symptoms — affects one in eight people. Scientists are still trying to decipher what is behind this heterogeneous disease. Some studies point to immune dysfunction; others to viral reservoirs hiding in the body. Researchers also believe it is connected to persistent inflammation; but the fundamental mechanism remains unclear.

A study published on Thursday in the prestigious journal Science sheds light on the disease by identifying a potential biomarker in blood to detect long Covid. Researchers found that people with long Covid exhibited changes to blood serum proteins in the complement system, a network of molecules that participates in the destruction of pathogens. The finding highlights the key role the immune system plays in the development of long Covid and opens the door to drugs aimed at reversing this dysfunction in the body’s lines of defense.

By January 2020, the Sars-Cov-2 virus was already spreading silently around the globe and the first cases of Covid were beginning to break out everywhere. Four years later, around 778 million people have been infected, and seven million have died, according to the World Health Organization. But the thousands of people with long Covid are not included in the statistics. While they do not have an active infection, they suffer from symptoms such as fatigue, brain fog, muscle pain, breathing problems — sometimes all at once.

“There are currently no diagnostic tests or therapeutic solutions for affected patients,” admits the study in Science. There are no treatments or tests because long Covid is still, for scientists, a half-finished puzzle.

But researchers from the University of Zurich (Switzerland) have now managed to find another piece of the puzzle, and to identify a common pattern in long Covid. Scientists followed 39 healthy participants and 113 Covid patients for more than a year and took blood samples from all of them at different times to identify common biomarkers of people with long Covid. In the study, there were individuals who were infected with coronavirus, but did not have long Covid; others who had Covid symptoms for a few months after infection; and individuals who developed long Covid and experienced symptoms over time.

“We took blood from patients and looked at more than 6,500 different proteins. Then we asked ourselves what the biggest difference was and that was in the proteins that belong to the complement system,” explains Onur Boyman, author of the study and head of Clinical Immunology and Allergology at the Faculty of Medicine of the University of Zurich.

In people with long Covid, the scientists found that this mechanism — which is part of the innate immune system — was dysregulated. The complement system is a network of proteins that work in a cascade, activating each other to help recognize and destroy harmful elements. The problem is that if this mechanism is dysregulated, it can be harmful to the body. “This study showed that the complement system was active in long Covid: when patients have this condition, this system is also active. And what’s interesting is that in the group of patients with long Covid, there were some who were lucky and recovered. And in those cases, the complement system also returned to normal,” explains Boyman.

The scientist explains that the complement system not only communicates with the body’s immune system, but also with others, such as the blood coagulation system. In fact, researchers found that patients with long Covid had altered coagulation and tissue injury, which Boyman says could explain the presence of small blood clots. He explains: “The complement system also communicates with many different cells, for example, the cells inside blood vessels. If the complement system is active, those cells can become damaged. So, in an individual who has such damage to the endothelial cells [which line the inside of blood vessels], if you exercise, your heart pumps more, your blood pressure goes up, and that creates a stress on those endothelial cells. So, these cells have a double stress and this may explain exercise intolerance.”

The study does not specifically analyze whether the dysregulation of the complement system explains the varied mix of symptoms linked to long Covid, but Boyman points out that this network of proteins is in contact with the entire organism. “The complement system consists of small proteins that can travel in the blood to all organs: the brain, the lungs, the intestine… and these organs can interact with all types of cells. So in a normal situation, the complement system is fully active, not because we have a viral infection, but because this system has many different functions, such as removing dead cells. However, if you have a dysregulated complement system, it can cause damage and the extent of the damage can be very specific to the individual. In some people it can be the brain, in others the lungs, in the intestine… It depends on the person.”

Questions still to be answered

The research does not resolve all the questions surrounding long Covid, but, according to the external experts consulted, it does support the evidence that the immune system plays a key role in the disease.

“I wouldn’t say that [dysregulation of the complement system] is the cause, but rather a factor that could explain the symptoms that people with long Covid have. We don’t know if there are other things that could predict long Covid. This condition has always been hypothesized in different ways: a lot of tissue damage, a viral reservoir, or autoimmunity and inflammation. This work shows that the immune system has a lot to do with long Covid,” says Natalia Egri, an immunologist at Hospital Clínic, who was not involved in the research.

Jeremy Nicholson, director of the Australian National Phenome Center at Murdoch University, argues that the study “helps identify some fundamental immunological disruptions which help us understand the thrombo-inflammatory effects — affecting blood vessel linings for instance — which can give rise to more generalized systemic problems (all organs have blood vessels).” But he says, speaking to Science Media Centre, the paper “still does not explain the diversity of the long Covid symptoms or their differential expression between individuals.”

“This paper is another brick in the wall but the full integrative immune-metabolic picture of long Covid is yet to emerge and requires even more comprehensive studies in greater numbers of people,” he adds.

For his part, Marcos López-Hoyos, president of the Spanish Society of Immunology, points out that the research demonstrates that long Covid “is more linked to an alteration in the regulation of the immune response.” The expert, who also did not participate in the research, emphasizes that it is a “robust article, where many proteins are analyzed and there is a very well-controlled cohort.” But he also admits that the complement system “may not be the only factor” associated with long Covid. Boyman acknowledges that one of his major concerns is to find out “what keeps the complement system active” and why some patients with long Covid recover over time and others do not.

Possible treatment

The researchers suggest that their finding can serve as a biomarker to detect long Covid and also serve as a potential target for treatment. “There are companies that develop complement inhibitors. Currently, they are used for very rare immune diseases that affect the kidneys or muscles, for example. But this study could encourage those companies, which include big pharma, to address the treatment of long Covid,” says Boyman.

The researcher points out, however, that although the process of taking a sample is similar to an ordinary blood test, the subsequent study is more complex. “We use very complicated and sophisticated methods. You can’t just take our method and use it in any hospital to detect the differences we detect. It would take more development, but we have shown that this can be measured and a company that deals with diagnostics could develop a simpler test that could then be used in hospitals to improve the diagnosis of long Covid,” he says.

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