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Diagnosing long Covid: Have Cambridge researchers found the answer?



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Biomarkers in blood could be used to identify individuals who have had the Covid-19 virus months after infection, even if they had mild symptoms or none at all, according to Cambridge researchers.

They have received £370,000 from the National Institute for Health Research to develop a Covid-19 diagnostic test to complement existing antibody tests, along with one that could diagnose and monitor long Covid.

Dr Mark Wills, from the Department of Medicine at the University of Cambridge, who co-leads the team, said: “We need a reliable and objective way of saying whether someone has had Covid-19. Antibodies are one sign we look for, but not everyone makes a very strong response and this can wane over time and become undetectable.

Dr Mark Wills from the Department of Medicine at the University of Cambridge. Picture: University of Cambridge (49373833)
Dr Mark Wills from the Department of Medicine at the University of Cambridge. Picture: University of Cambridge (49373833)

“We’ve identified a cytokine that is also produced in response to infection by T cells and is likely to be detectable for several months – and potentially years – following infection.

“We believe this will help us develop a much more reliable diagnostic for those individuals who did not get a diagnosis at the time of infection.”

Most people recover from Covid-19 in days or weeks, but one in 10 develop symptoms that can last for months, irrespective of the severity of the symptoms they experienced..

Even individuals who were asymptomatic can experience long Covid, but diagnosing it is a challenge.

A patient with asymptomatic or mild disease may not have taken the gold standard PCR test while infected and therefore never had a confirmed diagnosis.

Antibody tests that look for immune cells produced in response to infection are thought to miss around 30 per cent of cases - particularly among those who have had only mild disease and or had the initial illness more than six months earlier.

The team at the University of Cambridge and Cambridge University Hospital NHS Foundation Trust will build on a pilot project supported by the Addenbrooke’s Charitable Trust. They have been recruiting patients from the Long Covid Clinic established in May 2020 at Addenbrooke’s.

Their pilot recruited 85 patients to the Cambridge NIHR Covid BioResource, a project that collects blood samples from patients when they are first diagnosed and again at intervals over several months.

The team hopes to expand this cohort to 500 patients recruited from Cambridgeshire and Peterborough.

Initial findings, which will soon be published, identified a biological fingerprint - a biomarker – in the blood of patients who had previously had Covid-19.

This molecule - a cytokine produced by T cells in response to infection - is known to persist in the blood.

The team hopes to answer questions by following patients for up to 18 months post-infection.

One of these is the key question of whether immunity wanes over time, which will inform our understanding of what booster vaccinations may be needed to maintain people’s protection.

The pilot study also identified a biomarker in long Covid patients. The research suggests these patients produce a second type of cytokine that persists in them for longer than in those who recover quickly.

This may be one of the drivers behind the many symptoms long Covid patients experience and could prove invaluable at diagnosing the condition.

Dr Nyarie Sithole, a consultant in infectious diseases and acute medicine at Addenbrooke’s Hospital. Picture: CUH (49373835)
Dr Nyarie Sithole, a consultant in infectious diseases and acute medicine at Addenbrooke’s Hospital. Picture: CUH (49373835)

Dr Nyarie Sithole, from the Department of Medicine at the University of Cambridge, who co-leads the team and helps to manage long Covid patients, said: “Because we currently have no reliable way of diagnosing long Covid, the uncertainty can cause added stress to people who are experiencing potential symptoms. If we can say to them ‘yes, you have a biomarker and so you have long Covid’, we believe this will help allay some of their fears and anxieties.

“There is anecdotal evidence that patients see an improvement in symptoms of long Covid once they have been vaccinated – something that we have seen in a small number of patients in our clinic. Our study will allow us to see how this biomarker changes over a longer period of time in response to vaccination.”

While the tests are being used at this stage for research, increasing the size of the cohort and carrying out further work could enable them to be optimised, scaled up and speeded up so that they are suitable for clinical diagnostic labs.

The research could hold the key to an in-depth understanding of how the immune system responds to infection by the SARS-CoV-2 virus and why it leads long Covid in some patients.

Dr Sithole added: “One of the theories of what’s driving long Covid is that it’s a hyperactive immune response – in other words, the immune system switches on at the initial infection and for some reason never switches off or never goes back to the baseline.

“As we’ll be following our patients for many months post-infection, we hope to better understand whether this is indeed the case.”

A further benefit of the work is that it could also help develop new treatments, since it could aid clinical trials that require an objective measurement of whether a drug is effective.

By assessing changes or the disappearance of long Covid-related cytokine biomarkers, along with improvements in symptoms, could indicate a treatment is working.

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