Centre for Inflammation Research

ICECAP findings and scientific outputs

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Unexpected mismatch between viral presence and organ inflammation in fatal COVID-19

Severe coronavirus disease 2019 (COVID-19) leads to life-threatening lung damage and high risk of death despite life support on a ventilator. COVID-19 is a new disease and we do not fully understand the process leading to lung damage: is it directly due to the presence of virus, or is the body's immune system causing damaging inflammation? Our ability to design and test specific treatments is limited until we answer this question.

Images showing viral presence inside lung tissue using fluorescent dyes.
Viral proteins in lung tissue are tagged with fluorescent dyes to confirm their presence..

The importance of post-mortem tissue studies

Many studies of the immune system in COVID-19 have used blood or lung washing samples. Whilst useful, these might not be representative of what is going on inside the lung tissue where the disease is most active. This limits our understanding of the disease even further. The virus has also been detected in organs other than the lung, but the consequences of this in terms of organ damage and function remain unknown. Investigating the mechanism of lung tissue damage, and involvement of other organs, is an urgent un-met need in understanding COVID-19. Understanding this will allow us to develop better tests and treatments for patients.

Hospital post-mortem examinations of people who have died from COVID-19 provide an opportunity to study the whole body in a level of detail not possible during life and answer these important clinical questions. To do this, we have assembled a multi-disciplinary team of clinicians and scientists, performing detailed analyses of multiple tissues obtained from post-mortem examinations.

Coronavirus is found in multiple organs

We find evidence of the COVID-19 virus in multiple sampled organs and tissues, most frequently in the lungs, but also from the gastrointestinal tract, heart and muscle, and less often from the liver, kidney and other organs. There was substantial variation between individual patients as to which organs contained virus at the time of death.

To provide higher resolution information, we then identified which specific cells the virus had infected. Generally, we found virus in the cells lining the respiratory tract, bowel, liver bile ducts and kidney urine concentrating tubes – all of these are made of epithelial cells. Interestingly, outside of the lung, the presence of virus was not associated with adjacent tissue damage or clinical features of organ dysfunction. For example, within the kidney the presence of virus was not associated with local inflammation, nor blood test evidence of kidney failure.

Two images of stained lung tissue, left showing abnormal blood vessels (vasculitis); right showing increased associated proteins
COVID-19 causes causes inflammation in blood vessels (vasculitis).

COVID-19 causes abnormal blood clotting and white blood cell behaviour

As we expected, tissue damage was mainly found in the lung, but we also found a universally abnormal response in organs of the immune system including the lymph nodes, spleen and bone marrow. In the lung, in addition to damage to the air sacs (alveoli), we identified blood vessel inflammation (vasculitis), which could contribute to the high frequency of blood clots seen in the lungs of patients with COVID-19. Significant findings in the immune system organs included abnormal macrophages (white blood cells involved in sensing and responding to pathogens, and tissue repair) and strikingly increased numbers of abnormal plasma cells (usually involved in producing antibodies). Whilst the consequences of these abnormalities are currently unknown, they identify specific cell types for further investigation. Detailed studies of cell types present within badly damaged lung tissue confirmed that macrophages and macrophage-like cells were increased in number and likely to be important.

Providing a foundation for future research

Overall, our findings provide a detailed atlas of where in the body the virus is present and how this associated with organ injury and abnormality. Importantly, this allows us to report a mismatch between the presence of virus and evidence of tissue damage and inflammation outside the lung. This suggests that treatments that reduce inflammation in the lung could be particularly effective in severe cases, since the virus alone may not be causing tissue damage. This is consistent with the beneficial effect of dexamethasone (a broad-spectrum anti-inflammatory drug) reported in the RECOVERY trial. In addition, we describe new types of inflammation in the lung that could contribute to lung failure in fatal COVID-19 (vasculitis) and identify specific immune cell types involved in the disease. This information could help identify new anti-inflammatory approaches for COVID-19. This research depends on the generosity of donors and their families who provide the valuable gift of tissue after death, and we are deeply grateful to them for this.

Image showing viral presence in many organs compared to inflammation, which is mostly limited to the lungs.
Intensity map showing presence of the virus (green) and sites of organ injury (orange).

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