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Title: An augmented passive immunotherapy for patients admitted to critical care with severe sepsis
Author: Morton, Ben
ISNI:       0000 0004 6059 7128
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2016
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Introduction: Antimicrobial resistance threatens to undermine treatment for severe infection; new therapeutic strategies are urgently needed. Pre-clinical work shows that augmented passive immunotherapy with P4 peptide increases phagocytic activity and shows promise as a novel therapeutic strategy. My aim was to determine how P4 peptide stimulation influenced ex vivo phagocytic cells from a target population of patients admitted to critical care with severe infection. Methods: Patients were prospectively recruited from two UK critical care units with severe sepsis. Clinical course was then observed (≥3 months post discharge). Blood samples were taken in early (≤48hrs post-diagnosis, n=54), latent (seven days post-diagnosis, n=39) and convalescent (3-6 months post-diagnosis, n=18) phases of disease. The primary outcome measure was killing of opsonised S.pneumoniae by neutrophils with and without P4 peptide stimulation. In addition, a flow cytometric whole blood phagocytosis assay was used to determine phagocyte association and oxidation of intraphagosomal reporter beads. Results: P4 peptide increased neutrophil killing of opsonised pneumococci by 8.6% (C.I. 6.35 . 10.76, p < 0.001) in all phases of sepsis, independent of infection source and microbiological status. This represented a 54.9% increase in bacterial killing compared to unstimulated neutrophils (15.6%) in early phase samples. Similarly, P4 peptide treatment significantly increased neutrophil and monocyte intraphagosomal reporter bead association and oxidation, independent of infection source. Conclusions: I have extended pre-clinical work to demonstrate that P4 peptide significantly increases phagocytosis and bacterial killing in samples from a target patient population with severe sepsis. This study supports the rationale for augmented passive immunotherapy as a therapeutic strategy in severe sepsis.
Supervisor: Gordon, S. B. ; Blakey, J. ; Welters, I. Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral