A bench to bedside approach to factors influencing outcomes in community acquired pneumonia

Grudzinska, Frances Susanna ORCID: 0000-0002-0952-0163 (2024). A bench to bedside approach to factors influencing outcomes in community acquired pneumonia. University of Birmingham. Ph.D.

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Abstract

Community acquired pneumonia (CAP) is the leading cause of death from infectious disease in the UK, with more than 250,000 hospitalised episodes in adults each year. CAP predominantly affects older adults who frequently experience high burdens of mortality and morbidity in both short and long-term. CAP research thus far has focussed on antimicrobial therapy, or in people with CAP admitted to intensive care (ICU), only 5% of episodes in the UK involve an ICU admission. Older adults bear the brunt of CAP related morbidity and mortality, but they are underrepresented in research. This thesis aimed to explore factors influencing outcomes from CAP by using a multimodal approach with clinical data, statistical modelling and immunology with integrated bioinformatics. Chapter Two demonstrates that the pandemic significantly reduced hospitalisation with CAP in Birmingham, but those who were admitted had 50% increased mortality compared to the pre-pandemic period. During the pandemic hospitalised CAP was more severe, with increased rates of sepsis, but importantly care quality was not altered.
Chapter Three explores severity assessment in CAP, demonstrating that although CAP specific scores are more accurate at predicting adverse outcomes, CURB65 is impaired in people with multimorbidity. A novel score BCAPS was generated, BCAPS provides greater accuracy at prediction of 30-day mortality compared to CURB65. CAP requires a carefully orchestrated immune response, and particularly in older adults the neutrophil response is altered, which has been linked with adverse outcomes. Chapters 4-6 explore the role of neutrophils in CAP. Chapter Four describes optimisation and validation of extracellular flux technology to assess ex-vivo metabolism in isolated neutrophils. Given the short lifespan and propensity for activation of neutrophils this work was crucial for Chapter Five. This study also demonstrated that assessment of mitochondrial respiration in neutrophils is not possible using extracellular flux. Chapter Five is an observational cohort study which recruited 25 older adults with CAP and sepsis and 32 age and frailty matched controls. This study hypothesised that the altered neutrophil function seen in older adults with infection was due to impaired cellular energetics. Aberrant neutrophil function was demonstrated with altered migration, oxidative burst and degranulation in CAP participants, but ex-vivo rates of glycolysis were not changed. However, glycolysis was significantly different in younger adults compared to older adults with or without infection. Chapter Six demonstrates that RNAsequencing is feasible in isolated neutrophils and resulted in 760 differentially expressed genes, these genes offer novel targets for mechanistic investigation of neutrophil function. This data also demonstrated no difference in RNA expression of glycolytic enzymes or pathways. This thesis demonstrates an interdisciplinary approach to CAP. In future CAP research should focus on the needs of older adults, streaming together research disciplines to bring rapid impact by testing clinical interventions in accurately identified subgroups beside the pipeline of discovery science to provide the therapeutic targets of the future.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):