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Early immune system response may dictate path of Covid-19 for patients, Cambridge research finds



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A Covid-19 patient’s chances of suffering severe disease or long-term symptoms may be established early on by the immune system’s response, new Cambridge research suggests.

The findings, which have yet to be peer-reviewed, could have important implications for how doctors treat patients.

This scanning electron microscope image shows SARS-CoV-2 (orange) isolated from a patient in the US, emerging from the surface of cells cultured in the lab. Picture: National Institute of Allergy and Infectious Diseases-Rocky Mountain Laboratories, NIH
This scanning electron microscope image shows SARS-CoV-2 (orange) isolated from a patient in the US, emerging from the surface of cells cultured in the lab. Picture: National Institute of Allergy and Infectious Diseases-Rocky Mountain Laboratories, NIH

Scientists at the University of Cambridge and Addenbrooke’s Hospital have been recruiting individuals who have tested positive for the SARS-CoV-2 virus into the Covid-19 cohort of the NIHR BioResource.

These people ranged from asymptomatic healthcare workers in whom the virus was detected on routine screening to patients who required assisted ventilation in their battle against the virus.

Blood samples have been taken from the patients over several months and their symptoms monitored. They found:

those who were asymptomatic or had mild disease benefitted from a robust immune response early on during infection;

patients who required admission to hospital had impaired immune responses and systemic inflammation - meaning chronic inflammation potentially affecting several organs - from the time of symptom onset; and

persistent abnormalities in immune cells and a change in the body’s inflammatory response may contribute to what is being called ‘long Covid’.

Dr Paul Lyons, from Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), who is a senior co-author of the paper published on MedRXiv, said: “Our evidence suggests that the journey to severe Covid-19 may be established immediately after infection, or at the latest around the time that they begin to show symptoms.

“This finding could have major implications as to how the disease needs to be managed, as it suggests we need to begin treatment to stop the immune system causing damage very early on, and perhaps even pre-emptively in high risk groups screened and diagnosed before symptoms develop.”

It is understood that most people who get infected by SARS-CoV-2 have a successful antiviral response to it, meaning they suffer mild or no symptoms.

This scanning electron microscope image shows SARS-CoV-2 (yellow), the virus that causes Covid-19 - isolated from a patient in the US, emerging from the surface of cells (blue/pink) cultured in the lab. Image: National Institute of Allergy and Infectious Diseases-Rocky Mountain Laboratories, NIH (44084690)
This scanning electron microscope image shows SARS-CoV-2 (yellow), the virus that causes Covid-19 - isolated from a patient in the US, emerging from the surface of cells (blue/pink) cultured in the lab. Image: National Institute of Allergy and Infectious Diseases-Rocky Mountain Laboratories, NIH (44084690)

But in a minority, the immune system over-reacts and a ‘cytokine storm’ results, in which there is a flood of immune cells and chronic inflammation. This can damage multiple organs and lead to death.

The team analysed samples from 207 Covid-19 patients, who experienced different severities of disease and were interviewed regularly over three months from the onset of symptoms. The findings were compared against 45 healthy controls.

Professor Ken Smith, senior co-author and director of the CITIID, said: “The NIHR BioResource has allowed us to address two important questions regarding SARS-CoV-2. Firstly, how does the very early immune response in patients who recovered from disease with few or no symptoms, compare with those who experienced severe disease? And secondly, for those patients who experience severe disease, how rapidly does their immune system recover and how might this relate to ‘long COVID’?”

The results showed nearly all patients who experienced the disease, of whatever severity, had cleared the virus from their nasopharynx - behind the nose in the upper part of the throat - by three weeks following infection. Beyond that, symptoms seem to be driven by persistent inflammation.

Those who were asymptomatic or mildly symptomatic had a robust adaptive immune response, in which the body had identified the infection and produced T cells, B cells and specific antibodies to fight it. They produced these immune components in larger numbers than those patients who had more severe Covid-19, and they did so within the first week of infection. The numbers of these components then rapidly returned to normal, and there was no evidence of any systemic inflammation.

The researchers found a delay in the early adaptive immune response in those patients who required admission to hospital, and significant abnormalities in a number of white cell subsets.

In the first blood sample taken from these patients, there was also evidence of increased inflammation - suggesting the abnormal inflammatory component to the immune response is present as early as the time of diagnosis for those individuals who go on to suffer severe disease.

Key molecular signatures, produced in response to inflammation, were found in these patients admitted to hospital.

Crucially, there is the potential to use these signatures to predict the severity of a patient’s disease and correlate their risk of Covid-19 associated death.

They found no evidence of a relationship between a patient’s viral load - that is the amount of virus present in their system - and the progression to inflammatory disease. But for those in whom inflammatory disease set in, the viral load was associated with the outcome.

The research also offered some clues to ‘long Covid’ - which is where patients experience symptoms such as fatigue for months after the infection, even though they no longer test positive for the virus.

There were profound alterations in many immune cell types that last for weeks or months following infection in these patients.

This transmission electron microscope image shows SARS-CoV-2, the virus that causes Covid-19, isolated from a patient in the US. Virus particles are shown emerging from the surface of cells cultured in the lab. Image: NIAID-RML
This transmission electron microscope image shows SARS-CoV-2, the virus that causes Covid-19, isolated from a patient in the US. Virus particles are shown emerging from the surface of cells cultured in the lab. Image: NIAID-RML

Some immune cells recovered as the systematic inflammation resolved itself, while others recovered even while this remained a problem.

There were some cell populations, however, that continued to show abnormality or limited recovered even after the inflammation had gone away and the patients were discharged.

Dr Laura Bergamaschi, the study’s first author, said: “It’s these populations of immune cells that still show abnormalities even when everything else seems to have resolved itself that might be of importance in long Covid.

“For some cell types, it may be that they are just slow to regenerate, but for others, including some types of T and B cells, it appears something is continuing to drive their activity. The more we understand about this, the more likely we will be able to better treat patients whose lives continue to be blighted by the after-effects of Covid-19.”

The study is another example of the huge value of the NIHR BioResource.

Prof John Bradley, its chief investigator, who set up the Covid-19 cohort early on on the pandemic, said: “The NIHR BioResource is a unique resource made possible by the strong links that exist in the UK between doctors and scientists in the NHS and at our universities. It’s because of collaborations such as this that we have learnt so much in such a short time about SARS-CoV-2.”

Information has been collected from more than 6,000 people who want to be involved in Covid research, including 500 who have tested positive for the virus.

“We’re finding a wide range of longer-term problems including disorders of mood and brain function, respiratory symptoms, joint problems, fatigue, and issues relating to smell and taste,” said Prof Bradley, who is not keen on the “spectacularly imprecise” phrase of ‘long Covid’.

“These very different problems need different solutions, and lumping them together under the banner of ‘long Covid’ may make that more difficult to achieve,” he said. “Our research needs to focus on well-defined clinical problems that follow Covid-19 if we are to find solutions to help patients.”

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