̽��ֱ�� of Cambridge - Nyarie Sithole

Long COVID linked to persistently high levels of inflammatory protein: a potential biomarker and target for treatments

ta385 — Wed, 21 Feb 2024 18:45:00 +0000

A ̽��ֱ�� of Cambridge-led study identifies the protein interferon gamma (IFN-γ) as a potential biomarker for Long 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.

̽��ֱ��study, published today in Science Advances, followed a group of patients with Long COVID fatigue for over 2.5 years, to understand why some recovered and others did not.

Long COVID continues to affect millions of people globally and is placing a major burden on health services. An estimated 1.9 million people in the UK alone (2.9% of the population) were experiencing self-reported Long COVID as of March 2023, according to the ONS. Fatigue remains by far the most common and debilitating symptom and patients are still waiting for an effective treatment.

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

̽��ֱ��research began in 2020 when Dr Nyarie Sithole (Hughes Hall) set up a Long COVID clinic in Cambridge’s Addenbrooke’s Hospital, where he started collecting blood samples from patients and set about studying their immunology. Sithole soon enlisted the support of Dr Benjamin Krishna and Dr Mark Wills from the ̽��ֱ�� 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”.

̽��ֱ��team studied 111 COVID-confirmed patients admitted to Addenbrooke’s Hospital CUH, Royal Papworth Hospital and Cambridge and Peterborough NHS Foundation Trusts at 28 days, 90 days and 180 days following symptom onset. Between August 2020 and July 2021, they recruited 55 Long COVID patients – all experiencing severe symptoms at least 5 months after acute COVID-19 – attending the Long COVID clinic at Addenbrooke’s.

̽��ֱ��researchers analysed blood samples for signs of cytokines, small proteins crucial to the functioning of immune system cells and blood cells. They found that the white blood cells of individuals infected with SARS-CoV-2 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 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.”

By conducting ‘cell depletion assays’, the team managed to identify the precise cell types responsible for producing IFN-γ. They pinpointed immune cells known as CD8+ T cells but found that they required contact with another immune cell type: 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. Also, while previous studies have noticed IFN-y levels rising, they have not followed patients long enough to observe when they might drop back down.

̽��ֱ��Cambridge team followed its Long COVID cohort for up to 31 months post-infection. During this follow up period, over 60% of patients experienced resolution of some, if not all, of their symptoms which coincided with a drop in IFN-γ.

Vaccination helping Long COVID patients

̽��ֱ��team measured IFN-γ release in Long COVID patients before and after vaccination and found a significant decrease in IFN-γ post 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 may be helping to clear this. But we still need to find effective therapies,” Dr Krishna said.

“ ̽��ֱ��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.”

Microclotting

Some well-publicised previous studies have proposed microclotting as a principle cause of Long COVID. While not ruling out a role of some kind, these new findings suggest that microclotting cannot be the only or the most significant cause.

Classifying Long COVID

This study argues that the presence of IFN-γ could be used to classify Long COVID into subtypes which could be used to personalise treatment.

“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.

Reference

B A Krishna et al., ‘Spontaneous, persistent, T-cell dependent IFN-γ release in patients who progress to long COVID’, Science Advances (2024). DOI: 10.1126/sciadv.adi9379

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

We hope that this could help to pave the way to develop therapies and give some patients a firm diagnosis

Benjamin Krishna

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Woman sitting on sofa in the dark, placing a hand to her forehead

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Referrals to long COVID clinic fell by 79% following roll-out of the vaccine

cjb250 — Thu, 06 Oct 2022 07:00:15 +0000

According to the Office of National Statistics, in July this year an estimated 2 million people in the UK were living with self-reported long COVID – that is, symptoms continuing for more than four weeks after their first suspected coronavirus (COVID-19) infection. Patients report symptoms including fatigue, muscle aches, memory problems and shortness of breath more than six months post-acute COVID-19, and a significant number of patients have not fully recovered two years since the initial infection.

Two recent studies have suggested that vaccination strongly reduced long COVID symptoms one-to-three months after infection, but another study using a cohort of US Army Veterans suggested a more modest, 15% reduction at six months.

In May 2020, Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust (CUH), set up a long COVID clinic, with patients referred to the clinic based on a number of criteria, one of which is symptoms duration of at least five months. These patients tend to be those on the severe end of the symptom spectrum, having been referred following assessment by a team that includes a GP, mental health practitioners, physio and occupational therapists amongst other specialists.

Researchers at the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID) at the ̽��ֱ�� of Cambridge and CUH, analysed data from the clinic and found a 79% drop in the number of patients being referred to the clinic from August 2021 to June 2022, compared to August 2020 to July 2021. ̽��ֱ��decrease began five months after people started receiving second doses of COVID-19 vaccines.

Six-month moving averages fell from around 10 referrals per month to just one or two referrals per month. This effect has so far been sustained until at least June 2022, despite four times more cases per month of acute COVID-19 in England across the same time periods.

Dr Ben Krishna from the ̽��ֱ�� of Cambridge said: “Long COVID can have a significant impact on an individual’s life, and the large number of patients still experiencing symptoms many months after infection is placing additional strain on our healthcare services.

“We know that rollout of the vaccines has had a major impact on the number and severity of COVID infections, and evidence from our clinic suggests that it has also played an important role in reducing the rates of the most severe long COVID cases.”

̽��ֱ��researchers say that it is possible – but unlikely – that the emergence of the Delta variant may also have affected long COVID rates. However, the observed reduction in long COVID rates in August 2021 was from patients experiencing symptoms for five months, which they say would suggest a change beginning in March 2021. This correlates well with the second doses of vaccination in the UK, but the Delta wave did not begin until April 2021.

̽��ֱ��team say they also cannot rule out prior infections providing immunity that protects against long COVID from reinfections; however, primary infections were more common than reinfections around March-April 2021.

̽��ֱ��team observed no changes in symptoms between those referred for long COVID before or after vaccination for any of the major symptoms such as fatigue (73% pre-vaccination vs 76% post vaccination) and shortness of breath (18% pre-vaccination vs 23% post-vaccination).

It is not yet clear what level of immunity is required to protect against long COVID, say the researchers. As immunity wanes over time, booster shots – including variant-specific booster shots – may be necessary to minimise long COVID risk.

Dr Nyaradzai Sithole from CUH said: “As the virus continues to circulate and infect – and in many cases, re-infect – people, it’s important that everyone is up-to-date with their vaccinations. This will not only help prevent, or at least lessen, their primary COVID infection, but should reduce their risk of long COVID. But whether with the emergence of new variants we will begin to see an uptick in the number of cases of long COVID remains to be seen.”

̽��ֱ��study is published in Clinical Infectious Diseases.

̽��ֱ��research as funded by the Addenbrooke’s Charitable Trust and the National Institute for Health and Care Research (NIHR), with support from the NIHR Cambridge Biomedical Research Centre.

Reference
Krishna, B et al. Reduced incidence of Long COVID referrals to the Cambridge ̽��ֱ�� Teaching Hospital Long COVID clinic. Clinical Infectious Diseases; 1 Aug 2022; DOI: 10.1093/cid/ciac630

Referrals to Cambridge’s long COVID clinic fell dramatically in the period August 2021 to June 2022, which researchers say is likely due to the successful rollout of the vaccine.

We know that rollout of the vaccines has had a major impact on the number and severity of COVID infections, and evidence from our clinic suggests that it has also played an important role in reducing the rates of the most severe long COVID cases

Ben Krishna

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Model of coronavirus and hypodermic needle

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Biological ‘fingerprints’ of long COVID in blood could lead to diagnostic test, say Cambridge scientists

cjb250 — Mon, 19 Jul 2021 07:39:19 +0000

̽��ֱ��team has received funding from the National Institute for Health Research to develop a test that could complement existing antibody tests. They also aim to use similar biological signatures to develop a test and monitor for long COVID.

While most people recover from COVID-19 in a matter of days or weeks, around one in ten people go on to develop symptoms that can last for several months. This can be the case irrespective of the severity of their COVID-19 – even individuals who were asymptomatic can experience so-called ‘long COVID’.

Diagnosing long COVID can be a challenge, however. A patient with asymptomatic or mild disease may not have taken a PCR test at the time of infection – the gold standard for diagnosing COVID-19 – and so has never had a confirmed diagnosis. Even antibody tests – which look for immune cells produced in response to infection – are estimated to miss around 30% of cases, particularly among those who have had only mild disease and or beyond six months post-initial illness.

A team at the ̽��ֱ�� of Cambridge and Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust has received £370,000 from the National Institute for Health Research to develop a COVID-19 diagnostic test that would complement existing antibody tests and a test that could objectively diagnose and monitor long COVID.

̽��ֱ��research builds on a pilot project supported by the Addenbrooke’s Charitable Trust. ̽��ֱ��team has been recruiting patients from the Long COVID Clinic established in May 2020 at Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust.

During the pilot, the team recruited 85 patients to the Cambridge NIHR COVID BioResource, which collects blood samples from patients when they are first diagnosed and then at follow-up intervals over several months. They now hope to expand their cohort to 500 patients, recruited from Cambridgeshire and Peterborough.

In their initial findings, the team identified a biomarker – a biological fingerprint – in the blood of patients who had previously had COVID-19. This biomarker is a molecule known as a cytokine produced by T cells in response to infection. As with antibodies, this biomarker persists in the blood for a long time after infection. ̽��ֱ��team plans to publish their results shortly.

Dr Mark Wills from the Department of Medicine at the ̽��ֱ�� 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.

“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.”

By following patients for up to 18 months post-infection, the team hopes to address several questions, including whether immunity wanes over time. This will be an important part of helping understand whether people who have been vaccinated will need to receive boosters to keep them protected.

As part of their pilot study, the team also identified a particular biomarker found in patients with long COVID. Their work suggests these patients produce a second type of cytokine, which persists in patients with long COVID compared to those that recover quickly and might be one of the drivers behind the many symptoms that patients experience. This might therefore prove to be useful for diagnosing long COVID.

Dr Nyarie Sithole, also from the Department of Medicine at the ̽��ֱ�� 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.”

At the moment, the team is using the tests for research purposes, but by increasing the size of their study cohort and carrying out further work, they hope to adapt and optimise the tests that can be scaled up and speeded up, able to be used by clinical diagnostic labs.

As well as developing a reliable test, the researchers hope their work will help provide an in-depth understanding of how the immune system responds to coronavirus infection – and why it triggers long COVID in some people.

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.”

In addition, having a reliable biomarker could help in the development of new treatments against COVID. Clinical trials require an objective measure of whether a drug is effective. Changes in – or the disappearance of – long-COVID-related cytokine biomarkers with corresponding symptom improvement in response to drug treatment would suggest that a treatment intervention is working.

Markers in our blood – ‘fingerprints’ of infection – could help identify individuals who have been infected by SARS-CoV-2, the coronavirus that causes COVID-19, several months after infection even if the individual had only mild symptoms or showed no symptoms at all, say Cambridge researchers.

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

Nyarie Sithole

Annie Spratt

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When Symptoms Don't Stop

jg533 — Fri, 22 Jan 2021 08:13:29 +0000

Treating those most severely affected by COVID-19 has necessarily taken priority during the pandemic. But could long COVID be the next wave of the crisis?