Does hospitalisation of older patients with severe community acquired pneumonia and sepsis lead to long term immunoparesis?

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.

Our overarching aim is to test our hypothesis that an episode of CAP+S in patients over 50 years old causes age-related immunoparesis in both the innate and adaptive immune system that is driven by modification of gene expression in neutrophils, is persistent after hospital discharge, predisposes to secondary infection and maps to adverse longer term outcomes. To achieve this, we will conduct a experimental medicine / translational study in a cohort of CAP+S patients admitted to hospital recruited both in and outside ITU and will address the following research aims: 1. To assess CAP+S related changes in neutrophil and lymphocyte phenotype and function and to define the time course of changes induced by CAP+S. We will serially assess survivors to determine the persistence of these effects and their relationship to clinical outcomes. 2. To understand the mechanisms of any witnessed change. We will use advanced transcriptomic analysis of flow sorted neutrophils to identify variation in gene expression following CAP+S. The results will inform mechanistic and functional studies of relevant intracellular signalling pathways to relate the transcriptome signal to phenotype and function. 3. To determine whether immunoparesis following CAP+S reflects pre-existing immunoparesis in susceptible adults or develops de novo following infective insult, and to link immunoparesis to poor outcomes following secondary infection. We will assess how age related changes in mouse bone marrow neutrophils are influenced following an episode of acute infection and whether the persistence of these effects exaggerates the severity of a secondary bacterial challenge with S. Aureus.

WE BELIEVE THAT THIS RESEARCH IS IMPORTANT BECAUSE THE INCIDENCE OF PNEUMONIA AND SEPSIS IN THE UK IS RISING: Every year ~0.5-1% of adults in the UK will have community acquired pneumonia (CAP). It is diagnosed in 5-12% of adults who present to GPs with symptoms of lower respiratory tract infection, and 22-42% of these are admitted to hospital, where the overall mortality rate is between 5% and 14%. Between 1.2% and 10% of adults admitted to hospital with community acquired pneumonia are managed in an ICU, and for these patients the risk of dying is more than 30%. More than half of pneumonia related deaths occur in people older than 84 years - a group that are not often enrolled in clinical studies. Pneumonia hospitalizations are projected to nearly double by 2040 due to our aging population.

PNEUMONIA HAS BOTH SHORT AND LONG TERM IMPACTS ESPECIALLY IN OLDER PATIENTS.
Delirium is common among older people with pneumonia and associated with increased mortality and morbidity. Delerium is also associated with marked patient and carer distress. A reduction of disease severity in pneumonia could plausibly affect delirium and alleviate the adverse outcomes observed. The increasing incidence of both sepsis and pneumonia places additional burdens on the NHS since the median duration of stay in hospital increased with age: for those with a primary diagnosis of pneumonia, 6 days for those 65-74 years, 8 days for those 75-84 years, and 9 days for those >85 years(1).

Hospitalisation for pneumonia is associated with increased functional impairment in activities of daily living, mild-moderate cognitive impairment and substantial depressive symptoms. This results in the survivors of pneumonia and sepsis having increased care needs post hospital discharge (22% in our SNOOPI study), as well as a reported increase in post-discharge pneumonia and longer term mortality. Interventions that may reduce these observed declines could have significant impact upon patients health, quality of life, and NHS costs.

During this research we will characterise the changes in the innate and adaptive arms of the immune system acutely during CAP+S in older patients as well as determining whether these effects persist leading to exaggerated or enhanced age related immune dysfunction. This will provide new insight into the effects of sepsis in this important and under studied patient group and be of significant interest to the academic community and Pharma companies. Murine models will determine whether immune dysfunction precedes or is caused by the septic insult in age, helping to identify those most at risk of poor outcomes.

Second, mechanistic research will identify potential therapeutic approaches to improve neutrophil function by identifying important pathways that are involved in persistent dysfunction. We will also identify aspects of the adaptive immune system that might be amenable to modulation -such as vaccination, Ig supplementation or even antibiotic prophylaxis following the index admission for CAP+S. By deep functional / phenotyping our patients we should be able to develop ideas about how to personalise or stratify such therapy and provide major data about the influence of an episode of CAP+S upon older patients immunity. This will be of great interest to academic and industry partners, as well as the clinical community, where it will impact on clinical care in the medium to long term.

Impacts on the institution and wider economy: This research will also contribute to the reputation of the University of Birmingham as a centre for cutting edge translational research. The success of the centre has attracted academic industry contacts with both big pharma (GSK, AZ) as well as SMEs (e.g. Creabilis, Biopta). Further MRC funding should therefore enhance the reputation of the unit and draw more collaborators from industry promoting economic activity within Birmingham