Immune reactions to severe Covid may trigger brain problems, study finds

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Severe Covid infections can cause immune reactions that damage nerve cells in the brain, causing memory problems and confusion, and potentially raising the risk of long-term health issues, research suggests.

Scientists at King’s College London found that a wayward immune response to the virus increased the death rate of neurons and had a “profound” impact on regeneration in the hippocampus region of the brain, which is crucial for learning and memory.

The findings are preliminary but suggest Covid can trigger neurological problems in patients without the virus having to infect the brain itself. The process is believed to underpin delirium in Covid patients, but may also contribute to brain fog and other problems experienced by people with long Covid.

“These neurological symptoms are very concerning for patients and their families, and the hope is that our research can help identify which treatments would be most appropriate to lessen or prevent these symptoms,” said Carmine Pariante, a professor of biological psychiatry at KCL’s Institute of Psychiatry, and senior author on the study.

The researchers analysed blood from 36 Covid patients admitted to Guy’s and St Thomas’ NHS Foundation Trust in London in the first wave of the pandemic. They found that levels of a protein called IL-6, which immune cells release as a rallying call for other immune cells, were more than 15 times higher than normal in infected individuals.

But an even more dramatic rise in IL-6 was found in Covid patients with delirium – a state of extreme confusion that can leave people not knowing who, or where, they are. In these patients, IL-6 was six times higher than in other Covid patients. Nearly a third of Covid patients admitted to hospital experience delirium, rising to two-thirds in severe cases.

The scientists then investigated how high levels of IL-6 might affect neurons in the hippocampus by exposing lab-grown nerve cells to the patients’ blood. They found that blood from patients with delirium increased the normal death rate of neurons and reduced the generation of new brain cells. The damage caused is thought to drive delirium.

The harmful effects were traced back to a cascade of events where IL-6 triggers the release of two related immune proteins, called IL-12 and IL-13. Dr Alessandra Borsini, the study’s first author, said the impact of the proteins on generating new brain cells was “profound”.

However, blocking the proteins protected brain cells from damage, the scientists report in Molecular Psychiatry. The work suggests drugs known as Janus kinase inhibitors, which are already used to calm dangerous immune reactions to Covid, might combat delirium and its knock-on effects.

Older people are particularly vulnerable to delirium after a range of infections and operations. The state of confusion leads to a substantial rise in the risk of dementia.

“We believe these proteins are responsible for the delirium symptoms in acute Covid patients, and in general in long Covid patients experiencing neurological symptoms,” Borsini said. Measuring the levels of the immune proteins in patients could help personalise their treatment, she added.

Dr Thomas Jackson, a geriatrician who studies delirium and inflammation at the University of Birmingham, said: “What they’ve been able to show is that increased inflammation has a direct effect on brain cells which we know are linked to delirium and memory problems. The reduction in repair mechanisms and regeneration might begin to explain why people with delirium can have longer term cognitive problems.”

He said the same immune reaction may contribute to the “brain fog” some Covid patients report, which can persist for months after infection. But confirmation will need to come from further work, he said, such as the Covid-CNS study, which is investigating 800 UK patients who had neurological or neuropsychiatric complications from Covid.