A potential biomarker and target for treatments

SARS-CoV-2 triggers the production of the antiviral protein IFN-γ, which is associated with fatigue, muscle pain and depression. New research shows that in patients with long COVID, IFN-γ production persists until symptoms improve, highlighting a potential biomarker and target for therapies.

A study led by the University of Cambridge identifies the protein interferon gamma (IFN-γ) as a potential biomarker for prolonged COVID fatigue and highlights an immunological mechanism underlying the disease, which could pave the way for the development of much-needed therapies and provide a head start in the event of a future coronavirus pandemic.

The study, published in Scientists progress, followed a group of patients with long-term COVID fatigue for over 2.5 years, to understand why some recovered and others did not.

Long COVID continues to affect millions of people around the world and places a heavy burden on health services. An estimated 1.9 million people (2.9% of the population) in the UK alone (2.9% of the population) had self-reported long COVID in March 2023, according to the ONS. Fatigue remains by far the most common and debilitating symptom and patients are still awaiting effective treatment.

The study shows that initial infection with SARS-CoV-2 triggers the production of the antiviral protein IFN-γ, which is a normal reaction of the immune system. For most people, when their infection clears, COVID-19 symptoms stop and production of this protein stops, but researchers found that high levels of IFN-γ persisted in some patients with long COVID up to 31 months.

“We have discovered a potential mechanism underlying long COVID that could represent a biomarker, that is, a telltale signature of the disease. We hope this could help pave the way for the development of therapies and give some patients with a firm diagnosis.” said co-author Dr Benjamin Krishna of the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID).

The research began in 2020 when Dr Nyarie Sithole opened a long-running COVID clinic at Addenbrooke’s Hospital in Cambridge, where he began collecting blood samples from patients and studying their immunology. Sithole quickly gained the support of Dr. Benjamin Krishna and Dr. Mark Wills of the Department of Medicine at the University of Cambridge.

“When the clinic started, a lot of people didn’t even believe that long COVID was real,” Dr. Sithole said. “We are indebted to all the patients who volunteered for this study, without whose support and participation we obviously would not have carried out this study.”

The team studied 111 COVID-confirmed patients admitted to Addenbrooke’s CUH Hospital, Royal Papworth Hospital and Cambridge and Peterborough NHS Foundation Trusts 28 days, 90 days and 180 days after symptom onset . Between August 2020 and July 2021, they recruited 55 long COVID patients, all with severe symptoms at least five months after acute COVID-19, attending Addenbrooke’s long COVID clinic.

Researchers analyzed blood samples for signs of cytokines, small proteins that are essential for the functioning of immune system cells and blood cells. They found that white blood cells from SARS-CoV-2-infected individuals produced IFN-γ, a pro-inflammatory molecule, and that this persisted in long-COVID patients.

Dr Krishna said: “Interferon gamma can be used to treat viral infections such as hepatitis C, but it causes symptoms such as fatigue, fever, headache, muscle pain and depression. These symptoms are all too familiar to long COVID patients. For us, this was another irrefutable proof. »

By performing “cell exhaustion assays,” the team was able to identify the precise cell types responsible for IFN-γ production. They identified immune cells called CD8⁺ T cells but discovered that they required contact with another type of immune cell: CD14⁺ monocytes.

Previous studies have identified IFN-γ signatures using different approaches and cohorts, but this study’s focus on fatigue revealed a much stronger influence. Additionally, although previous studies have noticed an increase in IFN-γ levels, they have not followed patients long enough to observe when they might come back down.

The Cambridge team followed their Long COVID cohort for up to 31 months after infection. During this follow-up period, more than 60% of patients experienced resolution of some, if not all, of their symptoms, which coincided with a decline in IFN-γ levels.

Vaccination helps long-term COVID patients

The team measured IFN-γ release in long COVID patients before and after vaccination and found a significant decrease in post-immunization IFN-γ vaccination in patients whose symptoms resolved. .

“If SARS-CoV-2 continues to persist in people with long COVID, triggering an IFN-γ response, then vaccination could help address this problem. But we still need to find effective therapies,” said Dr. Krishna.

“The number of people with long COVID is gradually decreasing and vaccination appears to play an important role in this. But new cases continue to appear, and the big question then arises as to what will happen when the next coronavirus pandemic will arise. We could face another wave of long COVID. Understanding the causes of long COVID now could give us a crucial head start.

Some previous high-profile studies have proposed microcoagulation as the primary cause of long COVID.

Without ruling out any role, these new findings suggest that microcoagulation may not be the only or most important cause.

Classification of long COVID

This study supports that the presence of IFN-γ could be used to classify long COVID into subtypes that could be used to personalize treatment.

“It is unlikely that all the different long-lasting symptoms of COVID are caused by the same thing. We need to differentiate between people and tailor treatments. Some patients recover slowly and others get stuck in a cycle of tired for years. We need to know why,” said Dr. Krishna.