Interferon Gamma Persistence: Key Insights for Understanding Long COVID and Potential Treatments

SARS-CoV-2 triggers the production of an antiviral protein called IFN-γ, which is associated with symptoms such as fatigue, muscle ache, and depression. New research indicates that in Long COVID patients, this protein continues to be produced until their symptoms improve. This finding highlights a potential biomarker for identifying Long COVID and suggests a target for developing therapies.

A study led by the University of Cambridge has identified interferon gamma (IFN-γ) as a possible biomarker for long-lasting fatigue in those with Long COVID, uncovering an immunological mechanism underlying this condition. This research could pave the way for much-needed treatments and provide insights that may prove valuable during future pandemics.

The study, published today in Science Advances, followed a group of patients with Long COVID-related fatigue over more than 2.5 years to determine why some recovered while others did not. Long COVID affects millions globally and imposes a significant burden on healthcare services. According to the ONS as of March 2023, approximately 1.9 million people in the UK (representing about 2.9% of the population) were experiencing self-reported Long COVID symptoms.

Fatigue remains the most common and debilitating symptom experienced by patients with Long COVID, and there is currently no effective treatment available for this condition. The study reveals that when SARS-CoV-2 initially infects a person, it triggers the production of IFN-γ as part of their immune response. In most individuals, once they recover from the infection, symptoms subside along with reduced protein production.

However, researchers found that in some patients with Long COVID, high levels of IFN-γ persisted for up to 31 months after symptom onset. Dr. Benjamin Krishna, co-author and a member of the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), noted: “We have discovered a potential mechanism underlying Long COVID that could serve as a biomarker – essentially, a distinctive indicator of this condition. We hope that our findings will facilitate the development of therapies and provide some patients with more definitive diagnoses.”

The research began in 2020 when Dr. Nyarie Sithole (Hughes Hall) established a Long COVID clinic at Addenbrooke’s Hospital in Cambridge, where he started collecting blood samples from patients to examine their immune responses. He later collaborated with Drs Benjamin Krishna and Mark Wills from the University of Cambridge’s Department of Medicine.

“At the beginning, many people didn’t even believe that Long COVID was a real condition,” said Dr. Sithole. “We are extremely grateful for all our patients who volunteered to participate in this study, as their support has been instrumental in achieving these results.”

The team studied 111 confirmed COVID-19 cases admitted to Addenbrooke’s Hospital CUH, Royal Papworth Hospital, and Cambridge and Peterborough NHS Foundation Trusts at various intervals (28 days, 90 days, and 180 days) after symptom onset. Between August 2020 and July 2021, they recruited 55 patients with severe symptoms lasting for at least five months post-infection from the Long COVID clinic at Addenbrooke’s.

Researchers analyzed blood samples to identify signs of cytokines, which are crucial proteins involved in immune system function. They discovered that IFN-γ production continued elevated levels in those with persistent symptoms compared to individuals who had fully recovered.

The study also examined the impact of vaccination on Long COVID patients by measuring IFN-γ release before and after vaccinations. Significant decreases were observed post-vaccination among patients whose symptoms improved, suggesting a role for vaccination in mitigating SARS-CoV-2 persistence linked with increased IFN-γ response.

Dr Krishna commented: “If the virus continues to persist within individuals suffering from Long COVID by triggering an IFN-γ immune response, then vaccinations may be helping clear these cases. However, we still need more effective therapies. The number of people with Long COVID is gradually declining due to vaccination efforts; however, new cases are emerging continuously. Therefore, understanding the causes of Long COVID now will provide us with a vital head start for addressing any future pandemics.”

Microclotting: Although previous research has highlighted microclots as one possible cause of long-term symptoms associated with COVID-19 infection (Long COVID), this new study suggests that it is unlikely to be the sole or primary driver. It emphasizes that more comprehensive understanding and exploration into various underlying factors are necessary.

Classifying Long COVID: This research posits that measuring IFN-γ levels could help classify Long COVID into different subtypes, allowing for personalized treatments based on individual patients’ circumstances. Dr Krishna highlighted the importance of this approach by stating, “It’s unlikely that all Long COVID symptoms have a single cause. Differentiating between individuals and tailoring therapies according to their unique experiences will be crucial in understanding why some recover slowly while others remain trapped in cycles of fatigue for years.”