A recent study led by the University of Cambridge has identified the antiviral protein interferon gamma (IFN-γ) as a potential biomarker for fatigue in Long COVID patients. The research, published in Science Advances, tracked a group of individuals with Long COVID over more than two and a half years to investigate why some recovered while others continued to experience symptoms.
Long COVID remains a significant public health issue worldwide. In the United Kingdom alone, an estimated 1.9 million people reported experiencing Long COVID as of March 2023, according to data from the Office for National Statistics. Fatigue is reported as the most common and debilitating symptom among those affected.
The study found that SARS-CoV-2 infection triggers IFN-γ production as part of the immune response. While this response typically ends when infection clears, researchers observed that elevated levels of IFN-γ persisted in some Long COVID patients for up to 31 months after initial infection.
Dr Nyarie Sithole established a Long COVID clinic at Addenbrooke's Hospital in Cambridge in 2020 and began collecting blood samples from patients to study their immune responses. He was later joined by Dr Benjamin Krishna and Dr Mark Wills from the University of Cambridge's Department of Medicine.
"When the clinic started, a lot of people didn't even believe 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 would obviously not have accomplished this study".
The research team studied 111 confirmed COVID-19 patients at multiple hospitals at intervals following symptom onset and recruited 55 individuals with severe symptoms lasting at least five months after acute infection. Blood analyses revealed that white blood cells produced IFN-γ—a pro-inflammatory molecule—and that these levels remained high in those with persistent symptoms.
Dr Krishna noted: "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. These symptoms are all too familiar to Long COVID patients. For us, that was another smoking gun."
Further analysis identified CD8+ T cells as responsible for producing IFN-γ but only when interacting with CD14+ monocytes. The study also found that IFN-γ levels decreased alongside symptom improvement over time or after vaccination.
"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. But we still need to find effective therapies," Dr Krishna said.
"The number of people with Long COVID is gradually falling, and vaccination seems to be playing a significant role in that. 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. Understanding what causes Long COVID now could give us a crucial head start."
While previous studies have suggested microclotting as a primary cause for Long COVID symptoms, these findings indicate it may not be the sole or most significant factor.
The authors propose using IFN-γ presence to classify subtypes within Long COVID cases for more personalized treatment approaches.
"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," Dr Krishna said.
