The immune system and long COVID

Lung virus infection and coronavirus outbreak

Credit: wildpixel/GettyImages

The journey to severe or long COVID could be established immediately after infection, or at the latest when symptoms appear, according to new research.

The immune response associated with COVID-19 is complex. Most people who are infected mount a successful anti-viral response, which results in few, if any, symptoms.

In a minority of patients, however, there is evidence that the immune system overreacts. This leads to a flood of immune cells and to chronic inflammation and damage to multiple organs, often resulting in death.

Recruiting individuals

Scientists at the University of Cambridge and Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, have been recruiting individuals who test positive for SARS-CoV-2 to the COVID-19 cohort of the NIHR BioResource. They want to better understand the relationship between the immune response and COVID-19 symptoms.

These individuals range from asymptomatic healthcare workers to patients requiring assisted ventilation. The team takes blood samples from patients over several months, as well as continuing to measure their symptoms.

The key findings, which have not yet been peer-reviewed, are:

  • individuals who have asymptomatic or mild disease show a robust immune response early on during infection
  • patients requiring admission to hospital have impaired immune responses and systemic inflammation (that is, chronic inflammation that may affect several organs) from the time of symptom onset
  • persistent abnormalities in immune cells and a change in the body’s inflammatory response may contribute to ‘long COVID.’

Immune system response

Professor Ken Smith, senior co-author and Director of the Cambridge Institute of Therapeutic Immunology and Infectious Disease (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?

Preemptive treatment for high-risk groups

Dr Paul Lyons, senior co-author, also from 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 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.

The researchers found no evidence of a relationship between viral load and progression to inflammatory disease. However, once inflammatory disease was established, viral load was associated with subsequent outcome.


The study also provides clues to the biology underlying cases of long COVID. In long COVID patients report experiencing symptoms of the disease, including fatigue, for several months after infection, even when they no longer test positive for SARS-CoV-2.

The team found that profound alterations in many immune cell types often persisted for weeks or even months after SARS-CoV-2 infection. These problems resolved themselves very differently depending on the type of immune cell. Some recover while some 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 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 research was supported by:

  • UK Research and Innovation COVID Immunology Consortium
  • CVC Capital Partners
  • Evelyn Trust
  • Addenbrooke’s Charitable Trust
  • NIHR Cambridge Biomedical Research Centre
  • Wellcome.

Read about a new study into long-term impacts of lung damage after COVID-19.

Long COVID in the community

UK Research and Innovation (UKRI) and the National Institute for Health Research (NIHR) are funding four new research studies into ‘Long-COVID’ in the community.

The studies will help better understand the causes, symptoms and treatment of the condition and help address the physical and mental health effects of COVID-19 for people experiencing longer-term symptoms.

Over two million people in England could have long COVID: find out more.

Last updated: 11 July 2024

This is the website for UKRI: our seven research councils, Research England and Innovate UK. Let us know if you have feedback or would like to help improve our online products and services.