• Posted February 22, 2024

Scientists May Have Spotted a Key to Long COVID

Infection with the COVID-19 virus triggers the production of an immune system protein that's long been associated with fatigue, muscle ache and depression.

Trouble is, for folks suffering from Long COVID this protein overproduction does not stop, researchers at the University of Cambridge report.

“We have found a potential mechanism underlying Long COVID which could represent a biomarker -- that is, a tell-tale signature of the condition. We hope that this could help to pave the way to develop therapies and give some patients a firm diagnosis,” said study co-author Dr. Benjamin Krishna.

There was another silver lining from the research: Vaccination against SARS-Cov-2, the virus that causes COVID-19, appears to lower production of the culprit protein, called interferon gamma (IFN-γ).

“If SARS-CoV-2 continues to persist in people with Long COVID, triggering an IFN-γ response, then vaccination may be helping to clear this," said Krishna, who works at the Cambridge Institute of Therapeutic Immunology & Infectious Disease.

According to the latest data from the U.S. Centers for Disease Control and Prevention, almost 7% of Americans say they have experienced Long COVID. Most cite persistent fatigue as the major symptom, but Long COVID can also bring brain fog, chronic cough and other issues.

The exact causes of the illness have remained unclear.

In the latest study, Krishna's team tracked outcomes for 111 COVID patients admitted to U.K. health facilities. Patient symptoms were followed one month, three months and six months after diagnosis.

The researchers designated 55 of these patients as having Long COVID -- people who were "experiencing severe symptoms at least 5 months after acute COVID-19."

The Cambridge scientists analyzed blood samples from all of the patients, and found that infection with SARS-Cov-2 triggered a surge in production of the IFN-y protein in patients' white blood cells.

While IFN-y production eventually ebbed among folks whose COVID symptoms resolved, IFN-γ levels remained stubbornly high among those with Long COVID.

Krishna noted that interferon gamma's effects on people are already well-known, since it can be used as a medication.

“Interferon gamma can be used to treat viral infections such as hepatitis C, but it causes symptoms including fatigue, fever, headache, aching muscles and depression," Krishna noted in a Cambridge news release. "These symptoms are all too familiar to Long COVID patients. For us, that was another smoking gun.”

So, what's driving the COVID-linked uptick in IFN-y? Further research by Krishna's group showed that the interaction of two immune system cell types --  CD8+ T cells and CD14+ monocytes -- was key to protein overproduction.

Krishna stressed that these mechanisms may not be the only factors driving Long COVID. For example, prior studies have also pointed to "micro-clotting" as being a potential cause.

That makes sense, Krishna said, because “it's unlikely that all the different Long COVID symptoms are caused by the same thing. We need to differentiate between people and tailor treatments. Some patients are slowly recovering and there are those who are stuck in a cycle of fatigue for years on end. We need to know why."

He believes that checking a patient's blood levels of IFN-y might help doctors classify patients with a particular subtype of Long COVID, personalizing treatment.

When can folks expect their Long COVID to finally subside? In the study, researchers tracked the 55 Long COVID patients for up to 31 months. Over that time, 60% experienced a lessening of symptoms, which coincided with declining blood levels of IFN-y.

COVID-19 vaccination seemed to help, too. Blood tests taken from the Long COVID patients showed marked declines in blood levels of IFN-y after folks got the vaccine.

“The number of people with Long COVID is gradually falling, and vaccination seems to be playing a significant role in that," Krishna noted.

The findings were published Feb. 21 in the journal Science Advances.

"But new cases are still cropping up, and then there is the big question of what happens when the next coronavirus pandemic comes along. We could face another wave of Long COVID," he added. "Understanding what causes Long COVID now could give us a crucial head start.”

More information

Find out more about Long COVID at the National Institutes of Health.

SOURCE: University of Cambridge, news release, Feb. 21, 2024