Long Covid fatigue study in Cambridge identifies potential biomarker and target for therapies
A study led by the University of Cambridge has identified a potential biomarker for long Covid fatigue and identified a mechanism behind it that could be targeted by new therapies.
Some 1.9 million people in the UK - 2.9 per cent of the population - self-reported long Covid in March 2023, with fatigue being by far the most common and debilitating symptom.
The new study, published in Science Advances, shows that production of the antiviral protein IFN-y, which is triggered in our immune systems by the SARS-CoV-2 virus, persists in long Covid patients until symptoms improve. For some, high levels remained for 31 months.
“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 co-author Dr Benjamin Krishna, from the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID).
The research began in 2020 when Dr Nyarie Sithole set up a long Covid clinic at Addenbrooke’s and started collecting blood samples from patients and studying their immunology. He enlisted the help of 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,” said Dr Sithole. “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 team studied 111 patients with Covid admitted to Addenbrooke’s Hospital, Royal Papworth Hospital and Cambridge and Peterborough NHS Foundation Trust at 28 days, 90 days and 180 days following the onset of symptom onset.
They recruited 55 patients from the Addenbrooke’s clinic who experienced severe long Covid symptoms at least five months after acute Covid-19 between August 2020 and July 2021.
Their blood samples were analysed for signs of cytokines - small proteins key to the functioning of immune system cells and blood cells – and found white blood cells of individuals with SARS-CoV-2 produced IFN-γ, a pro inflammatory molecule. 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 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.”
They used cell depletion assays to identify the precise cell types responsible for producing IFN-γ, pinpointing immune cells known as CD8+ T cells, and learning that these required contact with another immune cell type - CD14+ monocytes.
While other studies have identified IFN-γ signatures using different approaches and cohorts, the focus of this study on fatigue demonstrated a far stronger influence, and the research was also the first to follow patients long enough to observe when levels dropped again.
In the follow-up period of up to 31 months, more than 60 per cent of patients experienced resolution of some, if not all, of their symptoms and this coincided with a drop in IFN-γ.
The team also found a significant decrease in IFN-γ post vaccination in long Covid patients whose symptoms resolved.
