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Likelihood of severe and ‘long’ COVID may be established very early on following infection

Published: 20 January 2021

Researchers supported by NIHR Cambridge Biomedical Research Centre set out to increase understanding of the relationship between the immune response and COVID-19 symptoms by recruiting individuals who tested positive COVID-19 into a cohort of the NIHR BioResource

They studied 207 people who tested positive for COVID-19 over a three-month period, taking blood samples and measuring their symptoms. They compared the samples with those taken from 45 healthy people.

The research shows that people with no symptoms or a mild case of COVID-19 mounted a robust immune response to the virus soon after getting infected. These individuals produced T cells, B cells and antibodies in larger numbers than patients with more severe COVID-19 and within the first week of infection – after which these numbers rapidly returned to normal. There was no evidence in these patients of widespread inflammation that can lead to damage in multiple organs. 

However, the people with severe COVID-19 who required hospitalisation had an impaired immune response, which led to a delayed and weakened attempt to fight the virus and widespread inflammation from the time of symptom onset.  In patients requiring admission to hospital, the early immune response was delayed, and profound abnormalities in a number of immune cells were present. 

Also, patients with severe COVID-19 had evidence of increased inflammation in their first blood sample, something not seen in those with asymptomatic or mild disease. This suggests that people who develop severe disease have an abnormal inflammatory immune response even at the time of diagnosis. 

The research, published on MedRXiv, specific molecular ‘signatures’ produced in response to inflammation in patients admitted to hospital. They say that these signatures could potentially be used to predict the severity of a patient’s disease, as well as correlating with their risk of COVID-19 associated death.

Dr Paul Lyons, senior co-author from the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), 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 we would 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.”

The study also provides clues to the biology underlying ‘long COVID’ – where patients report experiencing symptoms of the disease, including fatigue, for several months after infection, even when they no longer test positive for COVID-19.

The team found that profound alterations in many immune cell types often persisted for weeks or even months after COVID-19 infection, and these problems resolved themselves very differently depending on the type of immune cell. Some types of immune cells recover as widespread inflammation itself resolves, while others recover even in the face of persistent inflammation. However, some cell populations remain markedly abnormal, or show only limited recovery, even after systemic inflammation has resolved and patients have been discharged from hospital.

Dr Laura Bergamaschi, the study’s first author, said: “It’s these populations of immune cells, which 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.”

Professor John Bradley, Chief Investigator of the NIHR BioResource, 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 COVID-19.”


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