Does hospitalisation of older patients with severe community acquired pneumonia and sepsis lead to long term immunoparesis?
Description: Pneumonia is a serious lung infection. The 5th leading cause of death, each year 11 in every 1000 adults develop pneumonia outside of hospital, and 1 in 100 of those die. If the person is ill enough to be admitted to hospital, the death rate is much higher, and this rises considerably if a complication called sepsis develops. Sepsis is a syndrome whereby the infection causes changes to the body's natural immune system and ultimately cause damage to organs such as the lungs, brain and heart. Older people are more likely to develop pneumonia, have a higher risk of sepsis, and have worse outcomes (30 in 100 dying within 6 months).
The main treatment for pneumonia is antibiotics. Older adults often do not make a full recovery. An episode of pneumonia can lead to increased frailty, with the older person needing more social support or admission to a care home. Following pneumonia, older people are more susceptible to developing a subsequent (secondary) infection. These include another pneumonia, but also infections elsewhere in the body. Secondary infections have even worse outcomes but the reason older people are prone to them is unclear.
There are no treatments that help the immune system overcome pneumonia. Given that our population is ageing, this is an area of huge unmet need.
Neutrophils are white blood cells crucial for fighting infections. They leave the blood, moving (migrating) accurately to areas of infection, where they ingest bacteria, killing them with an arsenal of proteins contained within the cell. These proteins cause damage and inflammation if they are released outside of the cell into the body's tissues. In the face of overwhelming infection, neutrophils release their intracellular contents either directly into tissues (degranulation) or by releasing injurious proteins on a web of their own internal contents (like a fishing net) to trap and kill bacteria. Neutrophils contain genes that control the cell by dictating what proteins are expressed. These proteins could be enzymes, controlling chemical reactions within the neutrophil, or structural proteins, controlling how they move.
Other white blood cells help coordinate our immune system, by increasing neutrophil responses to make them clear infection or release their injurious contents more aggressively or dampening down their responses to promote healing. Cells involved in these controlling processes include B cell and T cell lymphocytes, which act as a memory of infections we have experienced in the past. B cells produce antibodies that promote the ingestion of bacteria and T cells coordinate local tissue responses, increasing inflammation and neutrophil activity at the start of an infection and promoting tissue healing after infection is cleared.
How immune cells function deteriorates with age. With ageing, our immune system becomes less able to differentiate "friend" (things that are safe) from "foe" (bacteria that will damage us). Our research shows that neutrophil migration, ingestion of bacteria and NET production become indiscriminate and inaccurate. Immune memory fades and our ability to respond quickly to infection but then heal, is blunted.
When older people develop pneumonia, immune function is compromised even further. Our research suggests that neutrophil migration and bacterial clearance is severely impaired for up to 6 weeks after pneumonia. We believe this paralysis of the immune system may lead to secondary infections.
We wish to investigate the long-term relevance of injurious neutrophil behaviours in pneumonia, using immune cells from patients with pneumonia and following recovery, and in models of infection. By studying B and T cells and how they interact with neutrophils, we will be able to determine the cause of the prolonged defective neutrophil behaviour, including the genes that control these cells. This will provide a new understanding of how our immune cells function in pneumonia and how we can improve outcome.
Funder: Medical Research Council
Amount: £524,700
Funding type: research
Start date: 2019-06-30
End date: 2023-06-29
Funded outputs count: 12
Funder award ID: MR/S002782/1
OpenAlex ID: G136247747